Heterocyclic compounds and uses thereof

ABSTRACT

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

This application claims priority to U.S. Provisional Application Nos.61/509,409, filed Jul. 19, 2011, 61/509,458, filed Jul. 19, 2011,61/509,474, filed Jul. 19, 2011, and 61/562,247, filed Nov. 21, 2011,the entireties of which are incorporated herein by reference.

BACKGROUND

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (e.g., PI3-kinases, PI4-Kinases),diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is also akey factor in many other diseases in humans. PI3K signaling is involvedin many disease states including allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique and conserved family of intracellularlipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. The PI3K family comprises 15kinases with distinct substrate specificities, expression patterns, andmodes of regulation. The class I PI3Ks (p110α, p110β, p110δ, and p110γ)are typically activated by tyrosine kinases or G-protein coupledreceptors to generate PIP3, which engages downstream effectors such asthose in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rhofamily GTPases. The class II and III PI3Ks play a key role inintracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.The PI3Ks are protein kinases that control cell growth (mTORC1) ormonitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).

The delta (δ) isoform of class I PI3K has been implicated, inparticular, in a number of diseases and biological processes. PI3K-δ isexpressed primarily in hematopoietic cells including leukocytes such asT-cells, dendritic cells, neutrophils, mast cells, B-cells, andmacrophages. PI3K-δ is integrally involved in mammalian immune systemfunctions such as T-cell function, B-cell activation, mast cellactivation, dendritic cell function, and neutrophil activity. Due to itsintegral role in immune system function, PI3K-δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, and auto-immune diseases such aslupus, asthma, emphysema and other respiratory diseases. Other class IPI3K involved in immune system function includes PI3K-γ, which plays arole in leukocyte signaling and has been implicated in inflammation,rheumatoid arthritis, and autoimmune diseases such as lupus.

Unlike PI3K-δ, the beta (β) isoform of class I PI3K appears to beubiquitously expressed. PI3K-β has been implicated primarily in varioustypes of cancer including PTEN-negative cancer (Edgar et al. CancerResearch (2010) 70(3):1164-1172), and HER2-overexpressing cancer such asbreast cancer and ovarian cancer.

SUMMARY

Described herein are compounds capable of selectively inhibiting certainisoform(s) of class I PI3K without substantially affecting the activityof the remaining isoforms of the same class. For example, non-limitingexamples of inhibitors capable of selectively inhibiting PI3K-δ and/orPI3K-γ, but without substantially affecting the activity of PI3K-β aredisclosed. Such inhibitors can be effective in ameliorating diseaseconditions associated with PI3K-δ/γ activity.

In one aspect, provided herein are compounds are provided of Formula(I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with0-4 occurrences of R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

wherein when W_(b) ⁵ is N, no more than one of X or Y is absent;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;and

W_(d) is

wherein X₁ is N or CR¹⁴;

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁷ are independently hydrogen,alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, carboxylic acid, oxo, orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

For example, the compound of Formula (II) can have a structure ofFormula (IIa) or (IIb):

In other embodiments, the compound of Formula (II) has the structure ofFormula (IIIa) or (IIIb):

For example, the compound of Formula (I) has the structure of Formula(IVa) or Formula (IVb):

In some embodiments, the compound of Formula (IVa) or Formula (IVb) hasthe structure of Formula (Va) or Formula (Vb):

In other embodiments, the compound of Formula (I) has the structure ofFormula (VIa) or Formula (VIb):

In other embodiments, the compound of Formula (VIa) or (VIb) has thestructure of Formula (VIIa) or (VIIb):

In some embodiments, the compound of Formula (VIIa) or (VIIb) has thestructure of Formula (VIIIa) or (VIIIb):

In some embodiments, the compound of Formula (VIIa) or (VIIb) has thestructure of Formula (IXa) or (IXb):

In another aspect, provided herein are compounds of Formula (X) or (XI):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or their pharmaceutically acceptable formsthereof, wherein:

W_(b) ⁵ is N, CHR⁸, or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro; wherein each of the abovesubstituents can be substituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is absent or is —(CH(R¹⁶))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁶)—, —C(═O)—(CHR¹⁶)_(z)—,—C(═O)—, —N(R¹⁶)—C(═O)—, or —N(R¹⁶)—C(═O)NH—, —N(R¹⁶)C(R¹⁶)₂—, or—C(═O)—N(R¹⁶)—(CHR¹⁶)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl; and

W_(d) is

wherein X₁ is N or CR¹⁴;

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁷ are independently hydrogenalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, carboxylic acid, oxo, orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety.

In a first aspect, provided herein are compounds of Formula (XII):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N,

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, arylor heteroaryl, each of which is substituted with 0-4 R²;

R² is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;and

W_(d) is

wherein one of X₅ and X₂ is N and one of X₅ and X₂ is C;

X₃ and X₄ are each independently CR¹³ or N;

X₂ and X₃ are not both N; and

each R¹⁰, R¹¹, R¹², R¹³, and R¹⁷ is independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, the compound of Formula (XII) has the structure ofFormula (XIII):

For example, the compound of Formula (XIII) can have a structure ofFormula (XIIIa) or (XIIIb):

In other embodiments, the compound of Formula (XIIIa) or (XIIIb) has thestructure of Formula (XIVa) or (XIVb):

For example, the compound of Formula (XII) has the structure of Formula(XVa) or Formula (XVb):

In some embodiments, the compound of Formula (XVa) or (XVb) has thestructure of Formula (XVIa) or Formula (XVIb):

In other embodiments, the compound of Formula (XII) has the structure ofFormula (XVIIa) or Formula (XVIIb):

In other embodiments, the compound of Formula (XVIIa) or (XVIIb) has thestructure of Formula (XVIIIa) or (XVIIIb):

In some embodiments, the compound of Formula (XVIIIa) or (XVIIIb) hasthe structure of Formula (XIXa) or (XIXb):

In some embodiments, the compound of Formula (XVIIIa) or (XVIIIb) hasthe structure of Formula (XXa) or (XXb):

In another aspect, provided herein is a compound of formula (XXI) or(XXII):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein:

W_(b) ⁵ is N, CHR⁸ or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R₁₅)—, —C(R₁₅)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro,phosphate, urea, carbonate, substituted nitrogen, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate,oxo, or NR′R″ wherein R′ and R″ are taken together with nitrogen to forma cyclic moiety;

X is absent or is —(CH(R⁹))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl; and

W_(d) is

wherein one of X₅ and X₂ is N and one of X₅ and X₂ is C;

wherein X₃ and X₄ are each independently selected from CR¹³ and N; and

each R¹⁰, R¹¹, R¹² and R¹³ is independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In another aspect, provided herein is a compound of Formula (XXIII):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

W_(b) ⁵ is N or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁶)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro,phosphate, urea, carbonate, substituted nitrogen, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate,urea, carbonate, or NR′R″ wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety;

X is absent or is —(CH(R¹⁴))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(O)₂—, —N(R⁹)—, —C(═O)—(CHR¹⁴)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R¹⁴)₂—, or—C(═O)—(CHR¹⁴)_(z);

each z is an integer of 1, 2, 3, or 4;

each R⁹ and R¹⁶ is independently hydrogen, alkyl, cycloalkyl,heterocyclyl, heteroalkyl, aryl, or heteroaryl;

each R¹⁴ and R¹⁵ is independently hydrogen, alkyl, aryl, heteroaryl orhalo; and

W_(d) is

wherein R¹⁰, R¹¹, R¹², and R¹⁷ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy,amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxy, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′ andR″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, the compound of Formula (XXIII) is a compound ofFormula (XXIV):

In one aspect, provided herein are compounds of Formula (XXV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR³, S, O, N or NR¹³, whereinat least one of W_(b) ¹ and W_(b) ² is CR³, N or NR¹³;

p is 0, 1, 2 or 3;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with0-4 occurrences of R²;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

wherein when W_(b) ⁵ is N, no more than one of X or Y is absent;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

each R³ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfonyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl which isoptionally substituted with one or more R^(b), R¹¹ or R¹²;

wherein each R^(b) is independently hydrogen, halo, phosphate, urea,carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, amino, heteroalkyl, orheterocyclyl; and

each R¹¹ and R¹² is independently hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro,phosphate, urea, carboxylic acid, carbonate, oxo, or NR′R″, wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, the compound of Formula (XXV) has a structure ofFormula (XXVI):

In some embodiments, the compound of Formula (XXVI) has a structure ofFormula (XXVIa) or (XXVIb):

In some embodiments, the compound of Formula (XXVI) has a structure ofFormula (XXVIIa) or (XXVIIb):

In certain embodiments, the compound of Formula (XXV) has a structure ofFormula (XXVIII):

In some embodiments, the compound of Formula (XXVIII) has a structure ofFormula (XXIX):

In certain embodiments, the compound of Formula (XXV) has a structure ofFormula (XXX):

In certain embodiments, the compound of Formula (XXX) has a structure ofFormula (XXXI):

In certain embodiments, the compound of Formula (XXX) has a structure ofFormula (XXXII):

In some embodiments, the compound of Formula (XXXII) has a structure ofFormula (XXXIII):

In another aspect, provided herein are compounds of Formula (XXXIV) or(XXXV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or their pharmaceutically acceptable formsthereof, wherein:

W_(b) ¹ and W_(b) ² are each independently CR³, S, O, N or NR¹³, whereinat least one of W_(b) ¹ and W_(b) ² is CR³, N or NR¹³;

p is 0, 1, 2 or 3;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;

X is absent or is —(CH(R¹⁶))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁶)—, —C(═O)—(CHR¹⁶)_(z)—,—C(═O)—, —N(R¹⁶)—C(═O)—, or —N(R¹⁶)—C(═O)NH—, —N(R¹⁶)C(R¹⁶)₂—, or—C(═O)—N(R¹⁶)—(CHR¹⁶)_(z);

each z is an integer of 1, 2, 3, or 4;

each R³ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R¹³ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl which isoptionally substituted with one or more R^(b), R¹¹ or R¹²;

wherein each R^(b) is independently hydrogen, halo, phosphate, urea,carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, amino, heteroalkyl, orheterocyclyl; and

each R¹¹ and R¹² is independently hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro,phosphate, urea, carboxylic acid, carbonate, oxo, or NR′R″, wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, a compound as disclosed herein selectivelymodulates phosphatidyl inositol-3 kinase (PI3 kinase) delta isoform. Incertain embodiments, the compound selectively inhibits the delta isoformover the beta isoform. By way of non-limiting example, the ratio ofselectivity can be greater than a factor of about 10, greater than afactor of about 50, greater than a factor of about 100, greater than afactor of about 200, greater than a factor of about 400, greater than afactor of about 600, greater than a factor of about 800, greater than afactor of about 1000, greater than a factor of about 1500, greater thana factor of about 2000, greater than a factor of about 5000, greaterthan a factor of about 10,000, or greater than a factor of about 20,000,where selectivity can be measured by I_(C50), among other means. Incertain embodiments, the PI3 kinase delta isoform I_(C50) activity of acompound as disclosed herein can be less than about 1000 nM, less thanabout 100 nM, less than about 10 nM, or less than about 1 nM.

In certain embodiments, provided herein is a composition (e.g., apharmaceutical composition) comprising a compound as described hereinand a pharmaceutically acceptable excipient. In some embodiments,provided herein is a method of inhibiting a phosphatidyl inositol-3kinase (PI3 kinase), comprising contacting the PI3 kinase with aneffective amount of a compound or pharmaceutical composition asdescribed herein. In certain embodiments, a method is provided forinhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) wherein saidPI3 kinase is present in a cell. The inhibition can take place in asubject suffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease. In certain embodiments, a secondtherapeutic agent is administered to the subject.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) delta isoform over PI3kinase beta isoform wherein the inhibition takes place in a cell.Non-limiting examples of the methods disclosed herein can comprisecontacting PI3 kinase delta isoform with an effective amount of acompound or pharmaceutical composition as disclosed herein. In anembodiment, such contact can occur in a cell.

In certain embodiments, a method is provided of selectively inhibiting aphosphatidyl inositol-3 kinase (PI3 kinase) delta isoform over PI3kinase beta isoform wherein the inhibition takes place in a subjectsuffering from a disorder selected from cancer, bone disorder,inflammatory disease, immune disease, nervous system disease (e.g., aneuropsychiatric disorder), metabolic disease, respiratory disease,thrombosis, and cardiac disease, said method comprising administering aneffective amount of a compound or pharmaceutical composition to saidsubject. In certain embodiments, provided herein is a method of treatinga subject suffering from a disorder associated with phosphatidylinositol-3 kinase (PI3 kinase), said method comprising selectivelymodulating the phosphatidyl inositol-3 kinase (PI3 kinase) delta isoformover PI3 kinase beta isoform by administering an amount of a compound orpharmaceutical composition to said subject, wherein said amount issufficient for selective modulation of PI3 kinase delta isoform over PI3kinase beta isoform.

In some embodiments, provided herein is a method of making a compound asdescribed herein.

In certain embodiments, provided herein is a reaction mixture comprisinga compound as described herein.

In certain embodiments, provided herein is a kit comprising a compoundas described herein.

In some embodiments, a method is provided for treating a disease ordisorder described herein, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

In some embodiments, a method is provided for treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of adisease or disorder described herein in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein for the treatment of a PI3Kmediated disorder in a subject.

In some embodiments, provided herein is a use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a disease or disorder described hereinin a subject.

In certain embodiments, provided herein is use of a compound or apharmaceutical composition described herein in the manufacture of amedicament for the treatment of a PI3K mediated disorder in a subject.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

DETAILED DESCRIPTION

In one embodiment, provided are heterocyclyl compounds, andpharmaceutically acceptable forms, including, but not limited to, salts,hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives thereof.

In another embodiment, provided are methods of treating and/or managingvarious diseases and disorders, which comprises administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof. Examples of diseases and disorders are described herein.

In another embodiment, provided are methods of preventing variousdiseases and disorders, which comprises administering to a patient inneed of such prevention a prophylactically effective amount of acompound provided herein, or a pharmaceutically acceptable form (e.g.,salts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. Examples of diseases and disorders are describedherein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, is administered incombination with another drug (“second active agent”) or treatment.Second active agents include small molecules and large molecules (e.g.,proteins and antibodies), examples of which are provided herein, as wellas stem cells. Other methods or therapies that can be used incombination with the administration of compounds provided hereininclude, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, and optionally one or more second active agents.

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

As used herein, “agent” or “biologically active agent” or “second activeagent” refers to a biological, pharmaceutical, or chemical compound orother moiety. Non-limiting examples include simple or complex organic orinorganic molecules, a peptide, a protein, an oligonucleotide, anantibody, an antibody derivative, an antibody fragment, a vitamin, avitamin derivative, a carbohydrate, a toxin, or a chemotherapeuticcompound, and metabolites thereof. Various compounds can be synthesized,for example, small molecules and oligomers (e.g., oligopeptides andoligonucleotides), and synthetic organic compounds based on various corestructures. In addition, various natural sources can provide compoundsfor screening, such as plant or animal extracts, and the like. A skilledartisan can readily recognize that there is no limit as to thestructural nature of the agents of this disclosure.

The term “agonist” as used herein refers to a compound or agent havingthe ability to initiate or enhance a biological function of a targetprotein or polypeptide, such as increasing the activity or expression ofthe target protein or polypeptide. Accordingly, the term “agonist” isdefined in the context of the biological role of the target protein orpolypeptide. While some agonists herein specifically interact with(e.g., bind to) the target, compounds and/or agents that initiate orenhance a biological activity of the target protein or polypeptide byinteracting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound or agent having the ability to inhibit abiological function of a target protein or polypeptide, such as byinhibiting the activity or expression of the target protein orpolypeptide. Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein orpolypeptide. While some antagonists herein specifically interact with(e.g., bind to) the target, compounds that inhibit a biological activityof the target protein or polypeptide by interacting with other membersof the signal transduction pathway of which the target protein orpolypeptide are also specifically included within this definition.Non-limiting examples of biological activity inhibited by an antagonistinclude those associated with the development, growth, or spread of atumor, or an undesired immune response as manifested in autoimmunedisease.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to subject so that both agentsand/or their metabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or pharmaceutical composition describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment, as illustrated below. Thetherapeutically effective amount can vary depending upon the intendedapplication (in vitro or in vivo), or the subject and disease conditionbeing treated, e.g., the weight and age of the subject, the severity ofthe disease condition, the manner of administration and the like, whichcan readily be determined by one of ordinary skill in the art. The termalso applies to a dose that will induce a particular response in targetcells, e.g., reduction of platelet adhesion and/or cell migration. Thespecific dose will vary depending on, for example, the particularcompounds chosen, the dosing regimen to be followed, whether it isadministered in combination with other agents, timing of administration,the tissue to which it is administered, and the physical delivery systemin which it is carried.

As used herein, the terms “treatment”, “treating”, “palliating” and“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including, but notlimited to, therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient can still be afflicted with the underlying disorder. Forprophylactic benefit, the pharmaceutical compositions can beadministered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A “modulator” of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator can augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or interact interaction with the target. Forexample, a compound that selectively inhibits one isoform of PI3K overanother isoform of PI3K has an activity of at least 2× against a firstisoform relative to the compound's activity against the second isoform(e.g., at least about 3×, 5×, 10×, 20×, 50×, or 100×).

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such as,but not limited to, alpha-particle emitting radionuclides (e.g.,actinium and thorium radionuclides), low linear energy transfer (LET)radiation emitters (i.e., beta emitters), conversion electron emitters(e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation,including without limitation x-rays, gamma rays, and neutrons.

“Subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, quail, and/or turkeys.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assayconducted outside of a subject. In vitro assays encompass cell-basedassays in which cells, alive or dead, are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

As used herein, “pharmaceutically acceptable esters” include, but arenot limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkylesters of acidic groups, including, but not limited to, carboxylicacids, phosphoric acids, phosphinic acids, sulfonic acids, sulfonicacids and boronic acids.

As used herein, “pharmaceutically acceptable enol ethers” include, butare not limited to, derivatives of formula —C═C(OR) where R can beselected from alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula —C═C(OC(O)R) where R can be selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.

As used herein, a “pharmaceutically acceptable form” of a disclosedcompound includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives of disclosed compounds. In one embodiment, a“pharmaceutically acceptable form” includes, but is not limited to,pharmaceutically acceptable salts, isomers, prodrugs and isotopicallylabeled derivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. In some embodiments, organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)⁴— salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

In certain embodiments, the pharmaceutically acceptable form is a“solvate” (e.g., a hydrate). As used herein, the term “solvate” refersto compounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or one toabout 2, about 3 or about 4, solvent or water molecules. It will beunderstood that the term “compound” as used herein encompasses thecompound and solvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. As used herein, the term “prodrug” refers to compounds that aretransformed in vivo to yield a disclosed compound or a pharmaceuticallyacceptable form of the compound. A prodrug can be inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis (e.g., hydrolysis in blood). Incertain cases, a prodrug has improved physical and/or deliveryproperties over the parent compound. Prodrugs are typically designed toenhance pharmaceutically and/or pharmacokinetically based propertiesassociated with the parent compound. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs isprovided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated in full byreference herein. Exemplary advantages of a prodrug can include, but arenot limited to, its physical properties, such as enhanced watersolubility for parenteral administration at physiological pH compared tothe parent compound, or it enhances absorption from the digestive tract,or it can enhance drug stability for long-term storage.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, New York, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₁-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H ormethyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” are different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. As used herein, the term “isomer” includesany and all geometric isomers and stereoisomers. For example, “isomers”include geometric double bond cis- and trans-isomers, also termed E- andZ-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and(l)-isomers, racemic mixtures thereof; and other mixtures thereof, asfalling within the scope of this disclosure.

Geometric isomers can be represented by the symbol

which denotes a bond that can be a single, double or triple bond asdescribed herein. Provided herein are various geometric isomers andmixtures thereof resulting from the arrangement of substituents around acarbon-carbon double bond or arrangement of substituents around acarbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(±)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is anenantiomer, the stereochemistry at each chiral carbon can be specifiedby either R or S. Resolved compounds whose absolute configuration isunknown can be designated (+) or (−) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at thewavelength of the sodium D line. Certain of the compounds describedherein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that can bedefined, in terms of absolute stereochemistry at each asymmetric atom,as (R)- or (S)-. The present chemical entities, pharmaceuticalcompositions and methods are meant to include all such possible isomers,including racemic mixtures, optically substantially pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers can beprepared, for example, using chiral synthons or chiral reagents, orresolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, e.g., the R enantiomer.ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 50%, about 75%, about 90%, about 95%, or about 99% of the Senantiomer. In other words, the compositions contain an enantiomericexcess of the S enantiomer over the R enantiomer. In other embodiments,some compositions described herein contain an enantiomeric excess of atleast about 50%, about 75%, about 90%, about 95%, or about 99% of the Renantiomer. In other words, the compositions contain an enantiomericexcess of the R enantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the percent by weightof one enantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than 1:1 byweight). For example, an enantiomerically enriched preparation of the Senantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the R enantiomer,such as at least about 75% by weight, further such as at least about 80%by weight. In some embodiments, the enrichment can be much greater thanabout 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least about 85% by weight of one enantiomer relative toother enantiomer, such as at least about 90% by weight, and further suchas at least about 95% by weight. In certain embodiments, the compoundprovided herein is made up of at least about 90% by weight of oneenantiomer. In other embodiments, the compound is made up of at leastabout 95%, about 98%, or about 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericpurity of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5% or more. In some other embodiments,the compound mixture has an (R)-enantiomeric excess of greater thanabout 55% to about 99.5%, greater than about 60% to about 99.5%, greaterthan about 65% to about 99.5%, greater than about 70% to about 99.5%,greater than about 75% to about 99.5%, greater than about 80% to about99.5%, greater than about 85% to about 99.5%, greater than about 90% toabout 99.5%, greater than about 95% to about 99.5%, greater than about96% to about 99.5%, greater than about 97% to about 99.5%, greater thanabout 98% to greater than about 99.5%, greater than about 99% to about99.5% or more.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities. In some embodiments, the mixture of identical chemicalentities is a racemic mixture of (S)- and (R)-isomers. In anotherembodiment, the mixture of the identical chemical entities (except fortheir stereochemical orientations), contain predominately (S)-isomers orpredominately (R)-isomers. For example, the (S)-isomers in the mixtureof identical chemical entities are present at about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,relative to the (R)-isomers. In some embodiments, the (S)-isomers in themixture of identical chemical entities are present at an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, the (R)-isomers in the mixture of identicalchemical entities (except for their stereochemical orientations), arepresent at about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, about 99.5%, or more, relative to the (S)-isomers. In someembodiments, the (R)-isomers in the mixture of identical chemicalentities (except for their stereochemical orientations), are present ata (R)-enantiomeric excess greater than about 55% to about 99.5%, greaterthan about 60% to about 99.5%, greater than about 65% to about 99.5%,greater than about 70% to about 99.5%, greater than about 75% to about99.5%, greater than about 80% to about 99.5%, greater than about 85% toabout 99.5%, greater than about 90% to about 99.5%, greater than about95% to about 99.5%, greater than about 96% to about 99.5%, greater thanabout 97% to about 99.5%, greater than about 98% to greater than about99.5%, greater than about 99% to about 99.5%, or more.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example,Enantiomers, Racemates and Resolutions (Jacques, Ed., WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, NY,1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertible compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a singlebond, or vice versa). “Tautomerization” includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. Tautomerizations (i.e., the reactionproviding a tautomeric pair) can be catalyzed by acid or base, or canoccur without the action or presence of an external agent. Exemplarytautomerizations include, but are not limited to, keto-to-enol;amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(adifferent) enamine tautomerizations. A specific example of keto-enoltautomerization is the interconversion of pentane-2,4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerizationis phenol-keto tautomerization. A specific example of phenol-ketotautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as ²H, ³H, ¹³C_(,) ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ¹⁸F, and³⁶Cl, respectively. Certain isotopically-labeled disclosed compounds(e.g., those labeled with ³H and ¹⁴C) are useful in compound and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can allow for ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) can afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). Isotopically labeled disclosed compoundscan generally be prepared by substituting an isotopically labeledreagent for a non-isotopically labeled reagent. In some embodiments,provided herein are compounds that can also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. All isotopic variations of the compounds as disclosedherein, whether radioactive or not, are encompassed within the scope ofthe present disclosure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions as disclosedherein is contemplated. Supplementary active ingredients can also beincorporated into the pharmaceutical compositions.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley& Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge UniversityPress, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₆alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 6, or1 to 3 carbon atoms. Representative saturated straight chain alkylsinclude, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl; while saturated branched alkyls include, butare not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl,-isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkylis attached to the parent molecule by a single bond. Unless statedotherwise in the specification, an alkyl group is optionally substitutedby one or more of substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CFCl₂, —CF₂Cl and the like.

“Alkyl-cycloalkyl” refers to an -(alkyl)cycloalkyl radical where alkyland cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkyl and cycloalkyl respectively. The“alkyl-cycloalkyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “alkenyl-cycloalkyl” and “alkynyl-cycloalkyl”mirror the above description of “alkyl-cycloalkyl” wherein the term“alkyl” is replaced with “alkenyl” or “alkynyl” respectively, and“alkenyl” or “alkynyl” are as described herein.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively. The “alkylaryl” is bonded to the parent molecularstructure through the alkyl group. The terms “-(alkenyl)aryl” and“-(alkynyl)aryl” mirror the above description of “-(alkyl)aryl” whereinthe term “alkyl” is replaced with “alkenyl” or “alkynyl” respectively,and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-heteroaryl” refers to an -(alkyl)heteroaryl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“alkyl-heteroaryl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heteroaryl” and“-(alkynyl)heteroaryl” mirror the above description of“-(alkyl)heteroaryl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Alkyl-heterocyclyl” refers to an -(alkyl)heterocycyl radical wherealkyl and heterocyclyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“alkyl-heterocyclyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heterocyclyl” and“-(alkynyl)heterocyclyl” mirror the above description of“-(alkyl)heterocyclyl” wherein the term “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and “alkenyl” or “alkynyl” are asdescribed herein.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₇-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group can consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the parent molecularstructure by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄) and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈) and the like. Unless stated otherwise in thespecification, an alkenyl group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a)), (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e., C₂-C₁₀alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group can consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to five carbon atoms (e.g., C₂-C₅alkynyl). The alkynyl is attached to the parent molecular structure by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like. Unless stated otherwise in the specification, an alkynylgroup is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 10carbon atoms of a straight, branched, cyclic configuration andcombinations thereof, attached to the parent molecular structure throughan oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, cyclohexyloxy and the like. “Lower alkoxy” refers toalkoxy groups containing one to six carbons. In some embodiments, C₁-C₄alkoxy is an alkoxy group which encompasses both straight and branchedchain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in thespecification, an alkoxy group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxy” and “alkynoxy” mirror the above description of “alkoxy”wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon having from 1 to 10 carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. The C₁-C₆ designationdoes not include the carbonyl carbon in the atom count. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkylportion of the alkoxy group is a lower alkyl group. In some embodiments,C₁-C₄ alkoxy is an alkoxy group which encompasses both straight andbranched chain alkoxy groups of from 1 to 4 carbon atoms. Unless statedotherwise in the specification, an alkoxycarbonyl group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxycarbonyl” and “alkynoxycarbonyl” mirror the above descriptionof “alkoxycarbonyl” wherein the prefix “alk” is replaced with “alken” or“alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁-C₁₀ acyl radical which refers to the totalnumber of chain or ring atoms of the, for example, alkyl, alkenyl,alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion plusthe carbonyl carbon of acyl. For example, a C₄-acyl has three other ringor chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise in thespecification, the “R” of an acyloxy group can be optionally substitutedby one or more substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, i.e., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring. For example, —N(R^(b)), is meant to include, but not be limitedto, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amino group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a)), (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The terms “amine” and “amino” also refer to N-oxides of the groups—N⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O—, R^(a) as described above,where the N-oxide is bonded to the parent molecular structure throughthe N atom. N-oxides can be prepared by treatment of the correspondingamino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(b), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, this radical is a C₁-C₄ amido or amide radical,which includes the amide carbonyl in the total number of carbons in theradical. When a —C(O)N(R^(b))₂ has two R^(b) other than hydrogen, theycan be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, N(R^(b))₂ portion of a —C(O)N(R^(b)),radical is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. Unless stated otherwise in the specification, an amidoR^(b) group is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

“Amidino” refers to both the —C(═NR^(b))N(R^(b)), and—N(R^(b))—C(═NR^(b))— radicals, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

“Aromatic” or “aryl” refers to a radical with six to ten ring atoms(e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,phenyl, fluorenyl, and naphthyl). For example, bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. In otherembodiments, bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., anaphthyl group with two points of attachment is termed naphthylidene.Whenever it appears herein, a numerical range such as “6 to 10 aryl”refers to each integer in the given range; e.g., “6 to 10 ring atoms”means that the aryl group can consist of 6 ring atoms, 7 ring atoms,etc., up to and including 10 ring atoms. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. Unless stated otherwise in the specification, an arylmoiety can be optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a)), (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively. The “aralkyl/arylalkyl” is bonded to theparent molecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

“Azide” refers to a —N₃ radical.

“Carbamate” refers to any of the following radicals: —O—(C═O)—N(R^(b))—,—O—(C═O)—N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))—(C═O)—OR^(b),wherein each R^(b) is independently selected from alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon) or heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Carbonate” refers to a —O—(C═O)—O— radical.

“Carbonyl” refers to a —(C═O)— radical.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” and “carbocyclyl” each refer to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and can be saturated orpartially unsaturated. Partially unsaturated cycloalkyl groups can betermed “cycloalkenyl” if the carbocycle contains at least one doublebond, or “cycloalkynyl” if the carbocycle contains at least one triplebond. Cycloalkyl groups include groups having from 3 to 10 ring atoms(i.e., C₃-C₁₀ cycloalkyl). Whenever it appears herein, a numerical rangesuch as “3 to 10” refers to each integer in the given range; e.g., “3 to10 carbon atoms” means that the cycloalkyl group can consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10carbon atoms. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures containing no heteroatoms. The term alsoincludes monocyclic or fused-ring polycyclic (i.e., rings which shareadjacent pairs of ring atoms) groups. In some embodiments, it is a C₃-C₈cycloalkyl radical. In some embodiments, it is a C₃-C₅ cycloalkylradical. Illustrative examples of cycloalkyl groups include, but are notlimited to the following moieties: C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅),cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl(C₆) and the like. Examples of C₃₋₈ carbocyclyl groups include theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples ofC₃₋₁₀ carbocyclyl groups include the aforementioned C₃₋₈ carbocyclylgroups as well as octahydro-1H-indenyl, decahydronaphthalenyl,spiro[4.5]decanyl and the like. Unless stated otherwise in thespecification, a cycloalkyl group is optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Cycloalkyl-alkyl” refers to a —(cycloalkyl)alkyl radical wherecycloalkyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkyl respectively. The“cycloalkyl-alkyl” is bonded to the parent molecular structure throughthe cycloalkyl group. The terms “cycloalkyl-alkenyl” and“cycloalkyl-alkynyl” mirror the above description of “cycloalkyl-alkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Cycloalkyl-heterocycloalkyl” refers to a —(cycloalkyl)heterocycylalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively. The “cycloalkyl-heterocycloalkyl” is bonded to the parentmolecular structure through the cycloalkyl group.

“Cycloalkyl-heteroaryl” refers to a —(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“cycloalkyl-heteroaryl” is bonded to the parent molecular structurethrough the cycloalkyl group.

As used herein, a “covalent bond” or “direct bond” refers to a singlebond joining two groups.

“Ester” refers to a radical of formula —COOR, where R is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl. Any amine, hydroxy,or carboxyl side chain on the compounds described herein can beesterified. The procedures and specific groups to make such esters areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporatedherein by reference in its entirety. Unless stated otherwise in thespecification, an ester group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ether” refers to a —R^(b)—O—R^(b)— radical where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the parent molecular structure can be througheither a heteroatom or a carbon in the heteroalkyl chain. For example,an N-containing heteroalkyl moiety refers to a group in which at leastone of the skeletal atoms is a nitrogen atom. One or more heteroatom(s)in the heteroalkyl radical can be optionally oxidized. One or morenitrogen atoms, if present, can also be optionally quaternized. Forexample, heteroalkyl also includes skeletal chains substituted with oneor more nitrogen oxide (—O—) substituents. Exemplary heteroalkyl groupsinclude, without limitation, ethers such as methoxyethanyl(—CH₇CH₇OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂OCH₂OCH₃), (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃) and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃) and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃) and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroalkyl-aryl” refers to a -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively. The“heteroalkyl-aryl” is bonded to the parent molecular structure throughan atom of the heteroalkyl group.

“Heteroalkyl-heteroaryl” refers to a -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively. The“heteroalkyl-heteroaryl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroalkyl-heterocycloalkyl” refers to a-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl respectively. The“heteroalkyl-heterocycloalkyl” is bonded to the parent molecularstructure through an atom of the heteroalkyl group.

“Heteroalkyl-cycloalkyl” refers to a -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively. The“heteroalkyl-cycloalkyl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a refers to aradical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic ortricyclic) aromatic ring system (e.g., having 6, 10 or 14 π electronsshared in a cyclic array) having ring carbon atoms and 1-6 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-18 membered heteroaryl”). Heteroaryl polycyclic ringsystems can include one or more heteroatoms in one or both rings.Whenever it appears herein, a numerical range such as “5 to 18” refersto each integer in the given range; e.g., “5 to 18 ring atoms” meansthat the heteroaryl group can consist of 5 ring atoms, 6 ring atoms,etc., up to and including 18 ring atoms. For example, bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical, e.g., a pyridyl group with two points of attachment is apyridylidene.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quaternized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocycyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). In some embodiments, a heteroaryl group is a 5-10 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous, and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5-8 membered heteroaryl”). In some embodiments, aheteroaryl group is a 5-6 membered aromatic ring system having ringcarbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimdinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl). Unless stated otherwise in the specification, a heteroarylmoiety is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))_(z),N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyland each of these moieties can be optionally substituted as definedherein.

“Heteroaryl-alkyl” refers to a -(heteroaryl)alkyl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“heteroaryl-alkyl” is bonded to the parent molecular structure throughany atom of the heteroaryl group.

“Heteroaryl-heterocycloalkyl” refers to an -(heteroaryl)heterocycloalkylradical where heteroaryl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heteroaryl and heterocycloalkylrespectively. The “heteroaryl-heterocycloalkyl” is bonded to the parentmolecular structure through an atom of the heteroaryl group.

“Heteroaryl-cycloalkyl” refers to an -(heteroaryl)cycloalkyl radicalwhere heteroaryl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“heteroaryl-cycloalkyl” is bonded to the parent molecular structurethrough a carbon atom of the heteroaryl group.

“Heterocyclyl”, “heterocycloalkyl” or ‘heterocarbocyclyl” each refer toany 3- to 18-membered non-aromatic radical monocyclic or polycyclicmoiety comprising at least one heteroatom selected from nitrogen,oxygen, phosphorous and sulfur. A heterocyclyl group can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein thepolycyclic ring systems can be a fused, bridged or spiro ring system.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. A heterocyclyl group can be saturated or partiallyunsaturated. Partially unsaturated heterocycloalkyl groups can be termed“heterocycloalkenyl” if the heterocyclyl contains at least one doublebond, or “heterocycloalkynyl” if the heterocyclyl contains at least onetriple bond. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range; e.g., “5 to 18 ringatoms” means that the heterocyclyl group can consist of 5 ring atoms, 6ring atoms, etc., up to and including 18 ring atoms. For example,bivalent radicals derived from univalent heterocyclyl radicals whosenames end in “-yl” by removal of one hydrogen atom from the atom withthe free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a piperidine group with twopoints of attachment is a piperidylidene.

An N-containing heterocyclyl moiety refers to an non-aromatic group inwhich at least one of the ring atoms is a nitrogen atom. Theheteroatom(s) in the heterocyclyl radical can be optionally oxidized.One or more nitrogen atoms, if present, can be optionally quaternized.Heterocyclyl also includes ring systems substituted with one or morenitrogen oxide (—O—) substituents, such as piperidinyl N-oxides. Theheterocyclyl is attached to the parent molecular structure through anyatom of any of the ring(s).

“Heterocyclyl” also includes ring systems wherein the heterocycyl ring,as defined above, is fused with one or more carbocycyl groups whereinthe point of attachment is either on the carbocycyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment to the parent molecular structure is on the heterocyclylring. In some embodiments, a heterocyclyl group is a 3-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous and sulfur (“3-10 membered heterocyclyl”).In some embodiments, a heterocyclyl group is a 5-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen,phosphorous and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen,oxygen phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen,phosphorous and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfonyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Heterocyclyl-alkyl” refers to a -(heterocyclyl)alkyl radical whereheterocyclyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“heterocyclyl-alkyl” is bonded to the parent molecular structure throughany atom of the heterocyclyl group. The terms “heterocyclyl-alkenyl” and“heterocyclyl-alkynyl” mirror the above description of“heterocyclyl-alkyl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Imino” refers to the “-(C═N)—R^(b)” radical where R^(b) is selectedfrom hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphonate” refers to a —O—P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a —P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable non-limiting examples of suchgroups unless otherwise specified include halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999),incorporated herein by reference in its entirety. For example, a hydroxyprotected form is where at least one of the hydroxy groups present in acompound is protected with a hydroxy protecting group. Likewise, aminesand other reactive groups can similarly be protected.

As used herein, the terms “substituted” or “substitution” mean that atleast one hydrogen present on a group atom (e.g., a carbon or nitrogenatom) is replaced with a permissible substituent, e.g., a substituentwhich upon substitution for the hydrogen results in a stable compound,e.g., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, or other reaction.Unless otherwise indicated, a “substituted” group can have a substituentat one or more substitutable positions of the group, and when more thanone position in any given structure is substituted, the substituent iseither the same or different at each position. Substituents include oneor more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein. For example, acycloalkyl substituent can have a halide substituted at one or more ringcarbons, and the like. The protecting groups that can form theprotective derivatives of the above substituents are known to those ofskill in the art and can be found in references such as Greene and Wuts,above.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S-” radical, and “arylthio” refers to the “aryl-S-” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁-C₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

Compounds

In one aspect, provided herein are compounds of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N,

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with0-4 occurrences of R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

wherein when W_(b) ⁵ is N, no more than one of X or Y is absent;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;and

W_(d) is

wherein X₁ is N or CR¹⁴;

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁷ are independently hydrogen,alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, carboxylic acid, oxo, orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety.

In certain embodiments, W_(b) ⁵ is CR⁸. In some embodiments, R⁸ ishydrogen.

In certain embodiments, Cy is aryl or heteroaryl substituted with 0-1occurrences of R³ and 0-3 occurrences of R⁵. In some embodiments, Cy isaryl or heteroaryl substituted with 0 occurrences of R³ and 0-3occurrences of R⁵. In some embodiments, Cy is aryl (e.g., phenyl)substituted with 0-1 occurrences of R³ and 0-3 occurrences of R⁵. Insome embodiments, Cy is phenyl substituted with 0-1 occurrences of R³and 0-3 occurrences of R⁵. In some embodiments, Cy is phenyl substitutedwith 0 occurrences of R³ and 0 occurrences of R⁵. In some embodiments,Cy is phenyl substituted with 1 occurrence of R³ and 0 occurrences ofR⁵. In some embodiments, R³ is alkyl (e.g., methyl). In someembodiments, R³ is halo (e.g., chloro or fluoro). In some embodiments,R³ is heteroaryl (e.g., 1-methyl-4-pyrazolyl, 2-methyl-5-pyrimidyl,2-methoxy-5-pyrimidyl, 2-amino-5-pyrimidyl, 2-amino-5-pyridyl,2,3-dimethyl-5-pyridyl, 3-methoxy-5-pyridyl, 5-pyrimidyl,5-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-4-pyridazinyl,2-methoxy-5-pyrimidyl or 1,3-dimethyl-4-pyrazolyl).

In some embodiments, In some embodiments, Cy is phenyl substituted with1 occurrence of R³ and 1 occurrence of R⁵. In some embodiments, R³ ishalo (e.g., chloro or fluoro) and R⁵ is halo (e.g., chloro or fluoro).

In certain embodiments, Cy is heteroaryl substituted with 0-1occurrences of R³ and 0-3 occurrences of R⁵. In some embodiments, Cy is5-membered heteroaryl (e.g., thiophenyl or isothiazolyl) substitutedwith 0-1 occurrences of R³ and 0-3 occurrences of R⁵. In someembodiments, Cy is thiophenyl substituted with 0 occurrences of R³ and 1occurrence of R⁵. In some embodiments, Cy is thiophenyl substituted with0-1 occurrence of R³ and 0 occurrence of R⁵. In some embodiments, Cy isthiophenyl substituted with 1 occurrence of R³ and 0 occurrence of R⁵.In some embodiments, Cy is isothiazolyl substituted with 0 occurrencesof R³ and I occurrence of R⁵. In some embodiments, Cy is isothiazolylsubstituted with 0-1 occurrence of R³ and 0 occurrence of R⁵. In someembodiments, Cy is isothiazolyl substituted with 1 occurrence of R³ and0 occurrence of R⁵. In some embodiments, Cy is 6-membered heteroaryl(e.g., pyridinyl).

In certain embodiments, B is hydrogen.

In certain embodiments, B is aryl (e.g., 6-membered aryl) substitutedwith 0-4 occurrences of R². In some embodiments, B is phenyl substitutedwith 0-4 occurrences of R². In some embodiments, B is phenyl substitutedwith 0 occurrences of R². In some embodiments, B is phenyl substitutedwith 1 occurrence of R². In some embodiments, R² is halo (e.g., fluoro).

In certain embodiments, B is cycloalkyl (e.g., cyclopropyl) substitutedwith 0-4 occurrences of R². In some embodiments, B is cyclopropylsubstituted with 0-4 occurrences of R². In some embodiments, B iscyclopropyl substituted with 0 occurrences of R².

In certain embodiments, B is alkyl (e.g., methyl) substituted with 0-4occurrences of R². In some embodiments, B is alkyl (e.g., methyl)substituted with 0 occurrences of R².

In some embodiments, X is —(CH(R⁹))_(z)—. In some embodiments, z is 1.In some embodiments, R⁹ is C₁₋₁₀ alkyl (e.g., methyl).

In some embodiments, is absent, —O—, —NH(R⁹)—, or —S(═O)_(z)—. Incertain embodiments, Y is absent. In some embodiments, Y is —N(R⁹)—. Insome embodiments, R⁹ is hydrogen.

In certain embodiments, X—Y is

In some embodiments, X—Y is —CH₂—N(CH₃). In some embodiments, X—Y is(S)—CH(CH₃)—NH—. In some embodiments, X—Y is (R)—CH(CH₃)—NH—.

In certain embodiments, X′ is N. In some embodiments, X¹ is CR¹⁴. Insome embodiments, R¹⁴ is hydrogen. In some embodiments, R¹⁴ is cyano.

In certain embodiments, R¹⁰ is hydrogen. In some embodiments, R¹⁰ ishalo (e.g., chloro). In some embodiments, R¹⁰ is amino. Non-limitingexamples include alkylamino groups, such as methylamino, ethylamino,propylamino, isopropylamino, butylamino, isobutylamino, pentylamino,isopentylamino, and hexylamino. In some embodiments, R¹⁰ is methylamino.In some embodiments, R¹⁰ is benzylamino, including optionallysubstituted benzylamino. In some embodiments, R¹⁰ is hydroxyl.

In certain embodiments, R¹¹ is hydrogen. In some embodiments, R¹² ishydrogen. In some embodiments, R¹³ is hydrogen. In some embodiments,R¹¹, R¹² and R¹³ are hydrogen.

In certain embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, Cy is aryl substituted with 0-1 occurrences of R³and 0-3 occurrences of R⁵. For example, Cy is phenyl substituted with 1occurrence of R³ and 0 occurrences of R⁵.

In other embodiments, Cy is heteroaryl substituted with 0-1 occurrencesof R³ and 0-3 occurrences of R⁵. For example, Cy is heteroarylsubstituted with 0-1 occurrences of R³ and 0-3 occurrences of R⁵. Insome embodiments, Cy is 5-membered heteroaryl substituted with 0-1occurrences of R³ and 0-3 occurrences of R⁵. In some embodiments, Cy isthiophenyl substituted with 0 occurrences of R³ and 1 occurrence of R⁵.In some embodiments, Cy is thiophenyl substituted with 0-1 occurrence ofR³ and 0 occurrence of R⁵. In some embodiments, Cy is thiophenylsubstituted with 1 occurrence of R³ and 0 occurrence of R⁵. In someembodiments, Cy is isothiazolyl substituted with 0 occurrences of R³ andI occurrence of R⁵. In some embodiments, Cy is isothiazolyl substitutedwith 0-1 occurrence of R³ and 0 occurrence of R⁵. In some embodiments,Cy is isothiazolyl substituted with 1 occurrence of R³ and 0 occurrenceof R⁵. In other embodiments, Cy is 6-membered heteroaryl.

In some embodiments of compounds of Formula (I), W_(d) is

In other embodiments of compounds of Formula (I), X is —(CH(R⁹))_(z)—.For example, z is 1.

In various embodiments, W_(d) is

wherein R¹⁰, R¹¹, R¹², and R¹³ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In some embodiments of the compound of Formula (I), at least one of R¹⁰,R¹¹, R¹² and R¹³ is hydrogen, cyano, halo, unsubstituted or substitutedalkyl, unsubstituted or substituted alkynyl, or unsubstituted orsubstituted alkenyl. In some embodiments, at least one of R¹⁰, R¹¹, R¹²and R¹³ is unsubstituted or substituted aryl. In some embodiments, atleast one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted or substitutedheteroaryl, which includes but is not limited to heteroaryl having afive membered ring, heteroaryl having a six membered ring, heteroarylwith at least one nitrogen ring atom, heteroaryl with two nitrogen ringatoms, monocylic heteroaryl, and bicylic heteroaryl. In someembodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted orsubstituted heterocyclyl, which includes but is not limited toheterocyclyl with one nitrogen ring atom, heterocyclyl with one oxygenring atom, heterocyclyl with one sulfur ring atom, 5 memberedheterocyclyl, 6 membered heterocyclyl, saturated heterocyclyl,unsaturated heterocyclyl, heterocyclyl having an unsaturated moietyconnected to the heterocyclyl ring, heterocyclyl substituted by oxo, andheterocyclyl substituted by two oxo. In some embodiments, at least oneof R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted or substituted cycloalkyl,including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloalkyl each of which can be substituted by one oxo;or cycloalkyl having an unsaturated moiety connected to the cycloalkylring. In some embodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ isunsubstituted or substituted amido, carboxylic acid, unsubstituted orsubstituted acyloxy, unsubstituted or substituted alkoxycarbonyl,unsubstituted or substituted acyl, or unsubstituted or substitutedsulfonamido. In some embodiments, R¹⁰, R¹¹, R¹², and R¹³ areindependently selected from hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, and hydroxyl. In some embodiments, R¹⁰, R¹¹,R¹², and R¹³ are independently selected from hydrogen, amino, andchloro. In some embodiments, R¹⁰ is selected from amino and chloro.

In some embodiments, when at least one of R¹⁰, R¹¹, R¹² and R¹³ isalkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substitutedwith one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro, each ofwhich alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido can itself be substituted.

In some embodiments of compounds of Formula (I), W_(d) is:

In some embodiments of compounds of Formula (I), W_(d) is a structureselected from:

In some embodiments, W_(d) is

and R¹⁰ is hydrogen, amino or halo. For example, W_(d) is

and R¹⁰ is Cl—. In another instance, W_(d) is

and R¹⁰ is hydrogen.

In some embodiments, Cy is aryl substituted with 0-1 occurrences of R³and 0-3 occurrences of R⁵. For example, Cy is phenyl substituted with 1occurrence of R³ and 0 occurrences of R⁵. In other embodiments, Cy isheteroaryl substituted with 0-1 occurrences of R³ and 0-3 occurrences ofR⁵. Cy can be, for example, pyridinyl, pyridazinyl, thiophenyl, furanyl,pyrrolyl, thiazolyl, or isothiazolyl. In some embodiments, Cy is5-membered heteroaryl substituted with 0-1 occurrences of R³ and 0-3occurrences of R⁵. In other embodiments, Cy is 6-membered heteroarylsubstituted with 0-1 occurrences of R³ and 0-3 occurrences of R⁵. Insome embodiments, Cy is aryl, thiophenyl, or isothiazolyl. In someembodiments, Cy is thiophenyl substituted with 0 occurrences of R³ and 1occurrence of R⁵. In some embodiments, Cy is thiophenyl substituted with0-1 occurrence of R³ and 0 occurrence of R⁵. In some embodiments, Cy isthiophenyl substituted with 1 occurrence of R³ and 0 occurrence of R⁵.In some embodiments, Cy is isothiazolyl substituted with 0 occurrencesof R³ and 1 occurrence of R⁵. In some embodiments, Cy is isothiazolylsubstituted with 0-1 occurrence of R³ and 0 occurrence of R⁵. In someembodiments, Cy is isothiazolyl substituted with 1 occurrence of R³ and0 occurrence of R⁵.

In some embodiments, the compound of Formula (I) has a structure ofFormula (II):

For example, the compound of Formula (II) can have a structure ofFormula (IIa) or (IIb):

In other embodiments, the compound of Formula (II) has the structure ofFormula (IIIa) or (IIIb):

In some embodiments, the compound of Formula (II) has a structure ofFormula (IIIb-1):

In some embodiments of compounds of Formula (IIa), (IIb), (IIIa),(IIIb), or (IIIb-1), W_(d) is

In some embodiments of compounds of Formula (IIa), (IIb), (IIIa),(IIIb), or (IIIb-1), W_(d) is a structure selected from:

In some embodiments of compounds of Formula (IIa), (IIb), (IIIa),(IIIb), or (IIIb-1), W_(d) is

and R¹⁰ is hydrogen, amino or halo. For example, W_(d) is

and R¹⁰ is Cl—. In another instance of a compound of Formula (IIa),(IIb), (IIIa), (IIIb), or (IIIb-1), W_(d) is

and R¹⁰ is hydrogen.

In some embodiments of compounds of Formula (IIa), (IIb), (IIIa),(IIIb), or (III-1), B is aryl substituted with 0-3 occurrences of R².For example, B is phenyl substituted with 0-3 occurrences of R². In someembodiments of compounds of Formula (IIa), (IIb), (IIIa), (IIIb), or(IIIb-1), B is unsubstituted phenyl. In other embodiments of compoundsof Formula (IIa), (IIb), (IIIa), (IIIb), or (IIIb-1), B is phenylsubstituted with 1 occurrence of R². R² is, in some instances, halo oralkyl. In other embodiments of compounds of Formula (IIa), (IIb),(IIIa), (IIIb), or (IIIb-1), B is cycloalkyl or heterocyclyl.

In still other embodiments, the compound of Formula (I) has a structureselected from:

In some embodiments, the compound of Formula (I) has the structure ofFormula (IVa) or Formula (IVb):

For example, the compound of Formula (IVa) or Formula (IVb) has thestructure of Formula (Va) or Formula (Vb):

In some embodiments, the compound of Formula (I) has a structure ofFormula (Va-1):

In some embodiments of compounds of Formula (IVa), (IVb), (Va), (Vb), or(Va-1), Wb⁵ is CR⁸. For example, Wb⁵ is CH. In some embodiments, thecompound is a compound of Formula (IVa), (IVb), (Va), (Vb), or (Va-1),where R³ is H. In other embodiments of a compound of Formula (IVa),(IVb), (Va), (Vb), or (Va-1), R⁵ is selected from hydrogen, alkyl,cycloalkyl, halo, aryl, and heteroaryl. For example, R⁵ is selected frommethyl, chloro or pyrazolo.

In some embodiments of compounds of Formula (IVa), (IVb), (Va), (Vb), or(Va-1), W_(d) is

In some embodiments of compounds of Formula (IVa), (IVb), (Va), (Vb), or(Va-1), W_(d) is a structure selected from:

In some embodiments of compounds of Formula (IVa), (IVb), (Va), (Vb), or(Va-1), W_(d) is

and R¹⁰ is hydrogen, amino or halo. For example, W_(d) is

and R¹⁰ is Cl—. In another instance of a compound of Formula (IVa),(IVb), (Va), (Vb), or (Va-1), W_(d) is

and R¹⁰ is hydrogen. In some embodiments of compounds of Formula (IVa),(IVb), (Va), (Vb), or (Va-1), B is aryl substituted with 0-3 occurrencesof R². For example, B is phenyl substituted with 0-3 occurrences of R².In some embodiments of compounds of Formula (IVa), (IVb), ((Va), (Vb),or (Va-1), B is unsubstituted phenyl. In other embodiments of compoundsof Formula (IVa), (IVb), (Va), (Vb), or (Va-1), B is phenyl substitutedwith 1 occurrence of R². R² is, in some instances, halo or alkyl. Inother embodiments of compounds of Formula (IVa), (IVb), (Va), (Vb), or(Va-1), B is cycloalkyl or heterocyclyl.

In other embodiments, the compound of Formula (I) has the structure ofFormula (VIa) or Formula (VIb):

In some embodiments of the compound of Formula (VIa) or (VIb), W_(d) is

In other embodiments, the compound of Formula (VIa) or (VIb) has thestructure of Formula (VIIa) or (VIIb):

In some embodiments, the compound of Formula (VIIa) or (VIIb) has thestructure of Formula (VIIIa) or (VIIIb):

In some embodiments, the compound of Formula (VIIa) or (VIIb) has thestructure of Formula (IXa) or (IXb):

In some embodiments, the compound of Formula (I) has a structure ofFormula (IXa-1):

In some embodiments, R³ is selected from alkyl, cycloalkyl, halo, aryl,and heteroaryl. For example, R³ is selected from methyl, chloro, andpyrazolo.

In some embodiments, B is aryl substituted with 0-3 occurrences of R².For example, B is phenyl substituted with 0-3 occurrences of R². B is,e.g., unsubstituted phenyl. Alternatively, B is phenyl substituted with1 occurrence of R². R² can be, for instance, halo or alkyl. In otherembodiments, B is cycloalkyl. In other embodiments, B is heterocyclyl.

For example, the compound of Formula (I) is a compound of Formula (VIa),(VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or (IXa-1), whereR³ is H. In other embodiments of a compound of Formula (VIa), (VIIa),(VIIIa), or (IXa), R³ is selected from hydrogen, alkyl, cycloalkyl,halo, aryl, and heteroaryl. For example, R³ is selected from methyl,chloro or pyrazolo. In some embodiments of compounds of Formula (VIa),(VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or (IXa-1), W_(d)is

In some embodiments of compounds of Formula (VIa), (VIb), (VIIa),(VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or (IXa-1), W_(d) is a structureselected from:

In some embodiments of compounds of Formula (VIa), (VIb), (VIIa),(VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or (IXa-1), W_(d) is

and R¹⁰ is hydrogen, amino or halo. For example, W_(d) is

and R¹⁰ is Cl—. In another instance of a compound of Formula (VIa),(VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or (IXa-1), W_(d)is

and R¹⁰ is hydrogen. In some embodiments of compounds of Formula (VIa),(VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or (IXa-1), B isaryl substituted with 0-3 occurrences of R². For example, B is phenylsubstituted with 0-3 occurrences of R². In some embodiments of compoundsof Formula (VIa), (VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb),or (IXa-1), B is unsubstituted phenyl. In other embodiments of compoundsof Formula (VIa), (VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb),or (IXa-1), B is phenyl substituted with 1 occurrence of R². R² is, insome instances, halo or alkyl. In other embodiments of compounds ofFormula (VIa), (VIb), (VIIa), (VIIb), (VIIIa), (VIIIb), (IXa), (IXb), or(IXa-1), B is cycloalkyl or heterocyclyl.

In another aspect, provided herein are compounds of Formula (X) or (XI):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein:

W_(b) ⁵ is N, CHR⁸, or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

R^(1′) is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(R¹⁵)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro; wherein each of the abovesubstituents can be substituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is absent or is —(CH(R¹⁶))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —N(R¹⁶)—, —C(═O)—(CHR¹⁶)_(z)—, —C(═O)—,—N(R¹⁶)—C(═O)—, or —N(R¹⁶)—C(═O)NH—, —N(R¹⁶)C(R¹⁶)₂—, or—C(═O)—N(R¹⁶)—(CHR¹⁶)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl; and

W_(d) is

wherein X₁ is N or CR¹⁴;

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁷ are independently hydrogen,alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, the compound is a compound of Formula (X). Forexample, the compound has the Formula:

In some embodiments, Cy is a 5- or 6-membered ring. In some embodiments,Cy is a 6-membered ring, such as a 6-membered aryl ring. For instance,Cy is a 6-membered ring, including e.g. phenyl. In other embodiments,W_(b) ⁵ is CH. In yet other embodiments, R¹¹ is H. In still otherembodiments, R¹² is H. In other embodiments, X—Y is —CH₂—N(CH₃).

In one aspect, provided herein are compounds are provided of Formula(I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with0-4 occurrences of R²;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—, —C(═O)—,—N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)_(z)—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

wherein when W_(b) ⁵ is N, no more than one of X or Y is absent;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;and

W_(d) is

wherein X₁ is N or CR¹⁴;

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁷ are independently hydrogen,alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, carboxylic acid, oxo, orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety.

In one aspect, provided herein are compounds of Formula (XII):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

W_(b) ⁵ is CR⁸, CHR⁸, or N,

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, arylor heteroaryl, each of which is substituted with 0-4 R²;

R² is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea or carbonate;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—, —C(═O)—,—N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;and

W_(d) is

wherein one of X₅ and X₂ is N and one of X₅ and X² is C;

X₃ and X₄ are each independently CR¹³ or N;

X₂ and X₃ are not both N; and

each R¹⁰, R¹¹, R¹², R¹³, and R¹⁷ is independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, W_(b) ⁵ is CR⁸. In some embodiments, R⁸ ishydrogen.

In certain embodiments, X³ is CR¹³. In some embodiments, R¹³ ishydrogen. In some embodiments, X³ is N.

In certain embodiments, X⁴ is CR¹³. In some embodiments, R¹³ ishydrogen. In some embodiments, X⁴ is N.

In some embodiments, Cy is aryl or heteroaryl substituted with 0-1occurrences of R³ and 0-3 occurrences of R⁵. In some embodiments, Cy isaryl or heteroaryl substituted with 0 occurrences of R³ and 0-3occurrences of R⁵. In some embodiments, Cy is aryl (e.g., phenyl)substituted with 0-1 occurrences of R³ and 0-3 occurrences of R⁵. Insome embodiments, Cy is phenyl substituted with 1 occurrence of R³ and 0occurrences of R⁵.

In some embodiments, Cy is heteroaryl substituted with 0-1 occurrencesof R³ and 0-3 occurrences of R⁵. In some embodiments, Cy is 5-memberedheteroaryl (e.g., thiophenyl or isothiazolyl) substituted with 0-1occurrences of R³ and 0-3 occurrences of R⁵. In some embodiments, Cy isthiophenyl substituted with 0 occurrences of R³ and I occurrence of R⁵.In some embodiments, Cy is thiophenyl substituted with 0-1 occurrence ofR³ and 0 occurrence of R⁵. In some embodiments, Cy is thiophenylsubstituted with 1 occurrence of R³ and 0 occurrence of R⁵. In someembodiments, Cy is isothiazolyl substituted with 0 occurrences of R³ and1 occurrence of R⁵. In some embodiments, Cy is isothiazolyl substitutedwith 0-1 occurrence of R³ and 0 occurrence of R⁵. In some embodiments,Cy is isothiazolyl substituted with 1 occurrence of R³ and 0 occurrenceof R⁵. In some embodiments, Cy is 6-membered heteroaryl (e.g.,pyridinyl).

In certain embodiments, R³ is halo (e.g, chloro). In some embodiments,R³ is heteroaryl (e.g., 1-methyl-4-pyrazolyl).

In some embodiments, X is —(CH(R⁹))_(z)—. In some embodiments, z is 1.In some embodiments, R⁹ is C₁₋₁₀ alkyl (e.g., methyl).

In some embodiments, is absent, —O—, —NH(R⁹)—, or —S(═O)₂—. In certainembodiments, Y is absent. In some embodiments, Y is —N(R⁹)—. In someembodiments, R⁹ is hydrogen.

In certain embodiments, X—Y is

In some embodiments, X—Y is —CH₂—N(CH₃). In some embodiments, X—Y is(S)—CH(CH₃)—NH—. In some embodiments, X—Y is (R)—CH(CH₃)—NH—.

In certain embodiments, B is aryl or heteroaryl substituted with 0-4occurrences of R². In some embodiments, B is aryl (e.g., 6-memberedaryl) substituted with 0-4 occurrences of R². In some embodiments, B isphenyl substituted with 0-4 occurrences of R². In some embodiments, B isphenyl substituted with 0 occurrences of R². In some embodiments, B isphenyl substituted with 1 occurrence of R². In some embodiments, R² isphenyl substituted at the ortho position. In some embodiments, R² isphenyl substituted at the meta position. In some embodiments, R² isphenyl substituted at the para position. In some embodiments, R² is halo(e.g., fluoro).

In certain embodiments, B is cycloalkyl substituted with 0-4 occurrencesof R². In some embodiments, B is cycloalkyl (e.g., cyclopropyl)substituted with 0 occurrences of R².

In certain embodiments, B is alkyl substituted with 0-4 occurrences ofR². In some embodiments, B is alkyl (e.g., methyl or ethyl) substitutedwith 0 occurrences of R². In some embodiments, B is alkyl (e.g., methylor ethyl) substituted with 1 occurrence of R². In some embodiments, R²is heterocyclyl (e.g., pyrrolyl).

In certain embodiments, X^(1 is) N and X² is C. In some embodiments, X¹is C and X² is N.

In certain embodiments, R¹⁰ is hydrogen. In some embodiments, R¹⁰ isalkyl (e.g., methyl).

In certain embodiments, R¹¹ is hydrogen.

In certain embodiments, R¹² is hydrogen. In some embodiments, R¹² ishalo (e.g., chloro).

In certain embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, R³ is halo, alkyl, alkoxy, heteroaryl, orcycloalkyl. For example, R³ is CH₃, CH₂CH₃, CF₃, Cl, or F. In otherembodiments, R³ is CH₃, CF₃, or Cl. In other embodiments, each R³ and R⁵is independently selected from CH₃, OCH₃, CF₃, and halo. In certainembodiments, R³ is halo (e.g., chloro). In some embodiments, R³ isheteroaryl (e.g., 1-methyl-4-pyrazolyl).

In some embodiments, B is cycloalkyl, heterocyclyl, aryl, or heteroaryl,which is substituted with 0-4 occurrences of R², R³ is H, halo, alkyl,alkoxy, aryl, cycloalkyl, or heteroaryl, each R⁵ is H, halo, alkyl,alkoxy, aryl, cycloalkyl, or heteroaryl, and R⁹ is hydrogen or alkyl.

In some embodiments. R⁵ is selected from alkyl, cycloalkyl, halo, aryl,and heteroaryl. For example, R⁵ is selected from methyl, chloro, andpyrazolo.

In various embodiments, W_(d) is

In such embodiments, X₃ is CR¹³ or N; each R¹⁰, R¹¹, R¹² and R¹³ isindependently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,or NR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety; and one of X₁ and X₂ is N and one of X₁ and X₂ is C.

For example, X₁ is N and X₂ is C. Alternatively, X₁ is C and X₂ is N. Insome embodiments, X₃ is CR¹³ or N. In other embodiments, X₄ is CR¹³ orN.

In some embodiments, X₃ is CR¹³. For example, R¹³ is H. In otherembodiments, X₃ is N.

In some embodiments, X₄ is CR¹³. For example, R¹³ is H. In otherembodiments, X₄ is N.

In some embodiments of the compound of Formula (I), at least one of R¹⁰,R¹¹, R¹² and R¹³ is hydrogen, cyano, halo, unsubstituted or substitutedalkyl, unsubstituted or substituted alkynyl, or unsubstituted orsubstituted alkenyl. In some embodiments, at least one of R¹⁰, R¹¹, R¹²and R¹³ is unsubstituted or substituted aryl. In some embodiments, atleast one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted or substitutedheteroaryl, which includes, but is not limited to, heteroaryl having afive membered ring, heteroaryl having a six membered ring, heteroarylwith at least one nitrogen ring atom, heteroaryl with two nitrogen ringatoms, monocylic heteroaryl, and bicylic heteroaryl. In someembodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted orsubstituted heterocyclyl, which includes, but is not limited to,heterocyclyl with one nitrogen ring atom, heterocyclyl with one oxygenring atom, heterocyclyl with one sulfur ring atom, 5 memberedheterocyclyl, 6 membered heterocyclyl, saturated heterocyclyl,unsaturated heterocyclyl, heterocyclyl having an unsaturated moietyconnected to the heterocyclyl ring, heterocyclyl substituted by oxo, andheterocyclyl substituted by two oxo. In some embodiments, at least oneof R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted or substituted cycloalkyl,including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloalkyl substituted by one oxo; or cycloalkyl having anunsaturated moiety connected to the cycloalkyl ring. In someembodiments, at least one of R¹⁰, R¹¹, R¹² and R¹³ is unsubstituted orsubstituted amido, unsubstituted or substituted acyloxy, unsubstitutedor substituted alkoxycarbonyl, unsubstituted or substituted acyl, orunsubstituted or substituted sulfonamido. In some embodiments, R¹⁰, R¹¹,R¹², and R¹³ are independently selected from hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, and hydroxyl. In someembodiments, R¹⁰, R¹¹, R¹² and R¹³ are independently selected fromhydrogen, amino, and chloro. In some embodiments, R¹⁰ is selected fromamino and chloro.

In some embodiments, when at least one of R¹⁰, R¹¹, R¹² and R¹³ isalkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substitutedwith one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each ofwhich alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido may itself be substituted.

In some embodiments, W_(d) is:

In some embodiments of compounds of Formula (I), W_(d) is a structureselected from:

In some embodiments, W_(d) is

and R¹² is hydrogen or halo.For example, W_(d) is

and R¹² is Cl. In another instance, W_(d) is

and R¹² is hydrogen.

In other embodiments, W_(d) is

and R¹⁰ is hydrogen or halo.

In still other embodiments, W_(d) is

For example, W_(d) is

In some embodiments, Cy is aryl substituted with 0-1 occurrences of R³and 0-3 occurrences of R⁵. For example, Cy is phenyl substituted with 1occurrence of R³ and 0 occurrences of R⁵. In other embodiments, Cy isheteroaryl substituted with 0-1 occurrences of R³ and 0-3 occurrences ofR⁵. Cy may be, for example, pyridinyl, pyridazinyl, thiophenyl, furanyl,pyrrolyl, thiazolyl, or isothiazolyl. In some embodiments, Cy is5-membered heteroaryl substituted with 0-1 occurrences of R³ and 0-3occurrences of R⁵. In other embodiments, Cy is 6-membered heteroarylsubstituted with 0-1 occurrences of R³ and 0-3 occurrences of R⁵. Insome embodiments, Cy is aryl, thiophenyl, or isothiazolyl. In someembodiments, Cy is thiophenyl substituted with 0 occurrences of R³ and 1occurrence of R⁵. In some embodiments, Cy is thiophenyl substituted with0-1 occurrence of R³ and 0 occurrence of R⁵. In some embodiments, Cy isthiophenyl substituted with 1 occurrence of R³ and 0 occurrence of R⁵.In some embodiments, Cy is isothiazolyl substituted with 0 occurrencesof R³ and 1 occurrence of R⁵. In some embodiments, Cy is isothiazolylsubstituted with 0-1 occurrence of R³ and 0 occurrence of R⁵. In someembodiments, Cy is isothiazolyl substituted with 1 occurrence of R³ and0 occurrence of R⁵.

In some embodiments, the compound of Formula (XII) has the structure ofFormula (XIII):

For example, the compound of Formula (I) can have a structure of Formula(XIIIa) or (XIIIb):

In other embodiments, the compound of Formula (XIIIa) or (XIIIb) has thestructure of Formula (XIVa) or (XIVb):

In some embodiments, the compound of Formula (XIII) has a structure ofFormula (XIVb-1):

In some embodiments of compounds of Formula (XIIIa), (XIIIb), (XIVa),(XIVb), or (XIVb-1), W_(d) is:

In some embodiments of compounds of Formula (XIIIa), (XIIIb), (XIVa),(XIVb), or (XIVb-1), W_(d) is:

In some embodiments of compounds of Formula (XIIIa), (XIIIb), (XIVa),(XIVb), or (XIVb-1), W_(d) is

and R¹² is hydrogen or halo. For example, W_(d) is

and R¹² is Cl— In another instance, W_(d) is

and R¹² is hydrogen.

In other embodiments of compounds of Formula (XIIIa), (XIIIb), (XIVa),(XIVb), or (XIVb-1), Wd is

and R¹⁰ is hydrogen or halo.

In still other embodiments of compounds of Formula (XIIIa), (XIIIb),(XIVa), (XIVb), or (XIVb-1), W_(d) is

For example, W_(d) is

In some embodiments of compounds of Formula (XIIIa), (XIIIb), (XIVa),(XIVb), or (XIVb-1), B is aryl substituted with 0-3 occurrences of R².For example, B is phenyl substituted with 0-3 occurrences of R². In someembodiments of compounds of Formula (XIIIa), (XIIIb), (XIVa), (XIVb), or(XIVb-1), B is unsubstituted phenyl. In other embodiments of compoundsof Formula (XIIIa), (XIIIb), (XIVa), (XIVb), or (XIVb-1), B is phenylsubstituted with 1 occurrence of R². R² is, in some instances, halo oralkyl. In other embodiments of compounds of Formula ((XIIIa), (XIIIb),(XIVa), (XIVb), or (XIVb-1), B is cycloalkyl or heterocyclyl.

In still other embodiments, the compound of Formula (XII) is a compoundwhich has a structure selected from:

In some embodiments, the compound of Formula (XIV) has the structure ofFormula (XVa) or Formula (XVb):

In other embodiments, the compound of Formula (XVa) or (XVb) is acompound of Formula (XVIa) or (XVIb):

In some embodiments, the compound of Formula (XII) has a structure ofFormula (XVIa-1):

In some embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), Wb⁵ is CR⁸. For example, W_(b) ⁵ is CH. In otherembodiments of a compound of Formula (XVa) or (XVb), R³ is selected fromalkyl, cycloalkyl, halo, aryl, and heteroaryl. For example, R³ isselected from methyl, chloro or pyrazolo.

In some embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), W_(d) is:

In some embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), W_(d) is a structure selected from:

In some embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), W_(d) is

and R¹² is hydrogen or halo. For example, W_(d) is

and R¹² is Cl—. In another instance, W_(d) is

and R¹² is hydrogen.

In other embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), Wd is

and R¹⁰ is hydrogen or halo.

In still other embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), W_(d) is

For example, W_(d) is

In some embodiments of compounds of Formula (XVa), (XVb), (XVIa),(XVIb), or (XVIa-1), B is aryl substituted with 0-3 occurrences of R².For example, B is phenyl substituted with 0-3 occurrences of R². In someembodiments of compounds of Formula (XVa), (XVb), (XVIa), (XVIb), or(XVIa-1), B is unsubstituted phenyl. In other embodiments of compoundsof Formula (XVa), (XVb), (XVIa), (XVIb), or (XVIa-1), B is phenylsubstituted with 1 occurrence of R². R² is, in some instances, halo oralkyl. In other embodiments of compounds of Formula (XVa), (XVb),(XVIa), (XVIb), or (XVIa-1), B is cycloalkyl or heterocyclyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (XVIIa) or (XVIIb):

In other embodiments, the compound of Formula (XVIIa) or (XVIIIb) hasthe structure of Formula (XVIIIa) or (XVIIIb):

In some embodiments, the compound of Formula (XVIIIa) or (XVIIIb) hasthe structure of Formula (XIXa) or (XIXb):

In some embodiments, the compound of Formula (XVIIIa) or (XVIIIb) hasthe structure of Formula (XXa) or (XXb):

In some embodiments, the compound of Formula (XII) has a structure ofFormula (XXa-1):

In some embodiments of a compound of Formula (XVIIa), (XVIIb), (XVIIIa),(XVIIIb), (XIXa), (XIXb), (XXa), (XXb), or (XXa-1), R³ is selected fromalkyl, cycloalkyl, halo, aryl, and heteroaryl. For example, R³ isselected from methyl, chloro or pyrazolo. In some embodiments ofcompounds of Formula (XVIIa), (XVIIb), (XVIIIa), (XVIIIb), (XIXa),(XIXb), (XXa), (XXb), or (XXa-1), W_(d) is:

In some embodiments of compounds of Formula (XVIIa), (XVIIb), (XVIIIa),(XVIIIb), (XIXa), (XIXb), (XXa), (XXb), or (XXa-1), W_(d) is a structureselected from:

In some embodiments of compounds of Formula (XVIIa), (XVIIb), (XIXa),(XIXb), (XXa), (XXb), or (XXa-1), W_(d) is

and R¹² is hydrogen or halo. For example, W_(d) is

and R¹² is Cl—. In another instance, W_(d) is

and R¹² is hydrogen.

In other embodiments of compounds of Formula (XVIIa), (XVIIb), (XVIIIa),(XVIIIb), (XIXa), (XIXb), (XXa), (XXb), or (XXa-1), W_(d) is

and R¹⁰ is hydrogen or halo.

In still other embodiments of compounds of Formula (XVIIa), (XVIIb),(XIXa), (XIXb), (XXa), (XXb), or (XXa-1), W_(d) is

For example, W_(d) is

In some embodiments of compounds of Formula (XVIIa), (XVIIb), (XIXa),(XIXb), (XXa), (XXb), or (XXa-1), B is aryl substituted with 0-3occurrences of R². For example, B is phenyl substituted with 0-3occurrences of R². In some embodiments of compounds of Formula (XVIIa),(XVIIb), (XVIIIa), (XVIIIb), (XIXa), (XIXb), (XXa), (XXb), or (XXa-1), Bis unsubstituted phenyl. In other embodiments of compounds of Formula(XVIIa), (XVIIb), (XVIIIa), (XVIIIb), (XIXa), (XIXb), (XXa), (XXb), or(XXa-1), B is phenyl substituted with I occurrence of R². R² is, in someinstances, halo or alkyl. In other embodiments of compounds of Formula(XVIIa), (XVIIb), (XVIIIa), (XVIIIb), (XIXa), (XIXb), (XXa), (XXb), or(XXa-1), B is cycloalkyl or heterocyclyl.

In some embodiments of the compound of Formula (XII), B is aryl orheteroaryl substituted with 0 or 1 occurrences of R² and Cy is a 5- or6-membered aryl or heteroaryl group. For example, B is aryl substitutedwith 0 or 1 occurrences of R² and Cy is a 5- or 6-membered aryl orheteroaryl group. In another example, B is aryl or heteroarylsubstituted with 0 or 1 occurrence of R² and Cy is a 6-membered arylgroup. Cy is, for instance, phenyl substituted with alkyl, fluoroalkyl,aryl, heteroaryl or halo. In such embodiments, W_(d) can be, forexample,

In other embodiments of the compound of Formula (XII), B is aryl orheteroaryl substituted with 0 or 1 occurrences of R², Cy is a 5- or6-membered aryl or heteroaryl group, X is —(CH(R⁹))_(z)— and Y is—NH(R⁹)—, wherein each R⁹ is chosen independently. For example, —X—Y— is—CH₂(CH₃)—NH—. In some embodiments, B is aryl substituted with 0 or 1occurrences of R² and Cy is a 5- or 6-membered aryl or heteroaryl group.In another example, B is aryl or heteroaryl substituted with 0 or 1occurrence of R² and Cy is a 6-membered aryl group. Cy is, for instance,phenyl substituted with alkyl, fluoroalkyl, aryl, heteroaryl or halo. Insuch embodiments, W_(d) can be, for example,

In some embodiments, the compound disclosed herein is a compound ofFormula (XIIIb) where R³ is halo, alkyl, heteroalkyl, fluoroalkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocyclyl; X is—CH(R⁹)—, where R⁹ is methyl or ethyl; R⁸ is H; Y is —NH—; and W_(d) is

In another aspect, provided herein is a compound of formula (XXI) or(XXII):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein:

W_(b) ⁵ is N, CHR⁸ or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R₁₅)—, —C(R₁₅)₂—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro,phosphate, urea, carbonate, substituted nitrogen, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R′⁷;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety;

X is absent or is —(CH(R⁹))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl; and

W_(d) is

wherein one of X₅ and X₂ is N and one of X₅ and X₂ is C;

wherein X₃ and X₄ are each independently selected from CR¹³ and N; and

each R¹⁰, R¹¹, R¹², R¹³, and R¹⁷ is independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, Cy is a 5- or 6-membered ring. For instance, Cy isa 6-membered ring, including e.g. phenyl. In other embodiments, Wb5 isCH. In yet other embodiments, R¹⁰, R¹¹, R¹², and R¹³ are H. In someembodiments, X—Y is —CH, —N(CH₃).

In some embodiments, Cy is a 6-membered ring, such as a 6-membered arylring. In other embodiments, W_(b) ⁵ is CH. In still other embodiments,—X—Y— is —CH, —N(CH₃).

In another aspect, provided herein is a compound of Formula (XXIII):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

W_(b) ⁵ is N or CR⁸;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³ and 0-3occurrences of R⁵;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁶)—, —C(R¹⁵)₂—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro,phosphate, urea, carbonate, substituted nitrogen, or NR′R″ wherein R′and R″ are taken together with nitrogen to form a cyclic moiety;

R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl,hydroxyl, or nitro; wherein each of the above substituents can besubstituted with 0, 1, 2, or 3 R¹⁷;

each R⁵ is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate,urea, carbonate, or NR′R″ wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety;

X is absent or is —(CH(R¹⁴))_(z);

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR¹⁴)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R¹⁴)₂—, or—C(═O)—(CHR¹⁴)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R⁹ and R¹⁶ is independently hydrogen, alkyl, cycloalkyl,heterocyclyl, heteroalkyl, aryl, or heteroaryl;

each R¹⁴ and R¹⁵ is independently hydrogen, alkyl, aryl, heteroaryl orhalo; and

W_(d) is

wherein R¹⁰, R¹¹, R¹², and R¹⁷ are independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy,amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxy, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′ andR″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, R⁵ is halo, alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, or heterocyclyl. In some embodiments, R⁵ isalkyl (e.g., methyl) or halo (e.g., chloro). In some embodiments, R⁵ ishalo (e.g., chloro).

In certain embodiments, n is 1 and L is —C(═O)— or —O—. In someembodiments, L is —C(═O)—.

In certain embodiments, R^(1′) is alkyl or NR′R″ wherein R′ and R″ aretaken together with nitrogen to form a cyclic moiety. In someembodiments, R′ and R″ are taken together with nitrogen to form aheterocyclic moiety (e.g., morpholinyl).

In certain embodiments, X is —(CH(R⁹))_(z)—. In some embodiments, zis 1. In some embodiments, X is —CH₂— or —CH(CH₃)—. In some embodiments,the carbon of the —CH(CH₃)— moiety has a (S) stereochemicalconfiguration. In some embodiments, the carbon of the —CH(CH₃)— moietyhas-a (R) stereochemical configuration.

In certain embodiments, Y is absent, —O—, —NH(R⁹)—, or —S(═O)₂—. In someembodiments, R⁹ is methyl or hydrogen.

In certain embodiments, —X—Y— is —CH₂—N(CH₃). In some embodiments, X—Yis (S)—CH(CH₃)—NH—. In some embodiments, —X—Y— is (R)—CH(CH₃)—NH—.

In certain embodiments, R¹⁰, R¹¹ and R¹² are independently selected fromhydrogen, amino, and chloro. In some embodiments, R¹⁰ is amino orchloro.

In some embodiments, Cy is aryl substituted with 0-3 occurrences of R⁵.For example, Cy is phenyl substituted with 1 occurrence of R³.

In some embodiments, R³ is halo, alkyl, heteroalkyl, fluoroalkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocyclyl. For example,R³ is alkyl or halo.

In other embodiments, L is —(C(═O)— or —O—.

In some embodiments, R¹′ is substituted alkyl, substituted nitrogen, orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety. For instance, the cyclic moiety is a heterocyclic orheteroaryl group such as a morpholino group. In other instances, R¹′ issubstituted alkyl, including alkyl which is substituted with aheterocyclyl group.

In some embodiments, X is absent or is —(CH(R⁹))_(z)—. In someembodiments, R⁹ is methyl or hydrogen. For example, z is 1. In someinstances, X is —CH₂— or —CH(CH₃)—. In some embodiments, the carbon ofthe —CH(CH₃)— moiety has a (S) stereochemical configuration.Alternatively, the carbon of the —CH(CH₃)— moiety has a (R)stereochemical configuration. In some embodiments, Y is absent, —O—,—NH(R⁹)—, or —S(═O)₂—. In some embodiments, —X—Y— is —CH₂—N(CH₃).Alternatively, —X—Y— is (S)—CH(CH₃)—NH— or (R)—CH(CH₃)—NH—.

In some embodiments, R¹⁰, R¹¹ and R¹² are independently selected fromhydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, and hydroxyl.For example, R¹⁰R¹¹ and R¹² are independently selected from hydrogen,amino, and chloro. In one instance, R¹⁰ is amino or chloro.

In some embodiments, Cy is aryl or heteroaryl group substituted by 0-1occurrences of R³ and 0-3 occurrences of R⁵. In some embodiments, Cy isaryl substituted with 0-1 occurrences or R³ and 0-3 occurrences of R⁵.For example, Cy is phenyl substituted with 1 occurrence of R³ and 0occurrences of R⁵. In other embodiments, Cy is phenyl substituted with 0occurrences of R³ and 0 occurrences of R⁵. In other embodiments, Cy isheteroaryl substituted with 0-1 occurrences of R³ and 0-3 occurrences ofR⁵. Cy can be, for example, pyridinyl, pyridazinyl, thiophenyl, furanyl,pyrrolyl, thiazolyl, or isothiazolyl. In some embodiments, Cy is5-membered heteroaryl substituted with 0-1 occurrences of R³ and 0-3occurrences of R⁵. In other embodiments, Cy is 6-membered heteroarylsubstituted with 0-1 occurrences of R³ and 0-3 occurrences of R⁵. Insome embodiments, Cy is aryl, thiophenyl, or isothiazolyl. For example,Cy is thiophenyl substituted with 0 occurrences of R³ and 1 occurrenceof R⁵. In another example, Cy is isothiazolyl substituted with 0occurrences of R³ and 1 occurrence of R⁵

In some embodiments or compounds of Formula (XXIII), R^(1′) can behydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate or NR′R″, wherein R′ and R″ are takentogether with nitrogen to form a cyclic moiety.

In some embodiments of compounds of Formula (XXIII), R^(1′) can behydrogen, or unsubstituted or substituted alkyl (including, but notlimited to, —CH₃, —CH₂CH₃, n-propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R^(1′) isunsubstituted or substituted alkenyl (including, but not limited to,unsubstituted or substituted C₂-C₅alkenyl such as, for example, vinyl,allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted orsubstituted alkynyl (including, but not limited to, unsubstituted orsubstituted C₂-C₅alkynyl such as acetylenyl, propargyl, butynyl, orpentynyl). Alternatively, R^(1′) is unsubstituted or substituted aryl(including, but not limited to, monocyclic or bicyclic aryl) orunsubstituted or substituted arylalkyl (including, but not limited to,monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes, butis not limited to, CH₃, —CH₂CH₃, n-propyl, isopropyl, n-butyl,sec-butyl, and pentyl). In some other embodiments, R^(1′) isunsubstituted or substituted heteroaryl, including, but not limited to,monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R^(1′)includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl,pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl,pyrazolyl, and oxazolyl. Bicyclic heteroaryl R^(1′) includes, but is notlimited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl,pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl,pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1, 2,4]triazinyl.

Also provided herein are compounds of Formula (XXIII) wherein R^(1′) isunsubstituted or substituted heteroarylalkyl, including, but not limitedto, monocyclic and bicyclic heteroaryl as described above, that arelinked to alkyl, which in turn includes, but is not limited to, CH₃,—CH₂CH₃, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In someembodiments, R^(1′) is unsubstituted or substituted cycloalkyl(including, but not limited to, cyclopropyl, cyclobutyl, andcyclopentyl) or unsubstituted or substituted heteroalkyl (non-limitingexamples include ethoxymethyl, methoxymethyl, and diethylaminomethyl).In some further embodiments, R^(1′) is unsubstituted or substitutedheterocyclyl which includes, but is not limited to, pyrrolidinyl,tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl,imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodimentsof the compounds of Formula (XXIII), R^(1′) is unsubstituted orsubstituted alkoxy including, but not limited to, C₁-C₄alkoxy such asmethoxy, ethoxy, propoxy or butoxy. R^(1′) can also be unsubstituted orsubstituted heterocyclyloxy, including but not limited to, 4-NHpiperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethylpiperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, andpyrrolidin-3-yl-oxy. In other embodiments, R^(1′) is unsubstituted orsubstituted amino, wherein the substituted amino includes, but is notlimited to, dimethylamino, diethylamino, di-isopropyl amino, N-methylN-ethyl amino, and dibutylamino. In some embodiments, R^(1′) isunsubstituted or substituted acyl, unsubstituted or substituted acyloxy,unsubstituted or substituted C₁-C₄acyloxy, unsubstituted or substitutedalkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted orsubstituted sulfonamido. In other embodiments, R^(1′) is halo, selectedfrom —I, —F, —Cl, and —Br. In some embodiments, R^(1′) is selected fromcyano, hydroxyl, nitro, phosphate, urea, or carbonate. In someembodiments, R^(1′) can be —CH₃, —CH₂CH₃, n-propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH₃, —OCH₂CH₃, or —CF₃.

In some embodiments, R^(1′) of the compounds of Formula (XXIII) can alsobe NR′R″ wherein R′ and R″ are taken together with the nitrogen to forma cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety soformed may further include one or more heteroatoms which are selectedfrom S, O, and N. The cyclic moiety so formed is unsubstituted orsubstituted, including, but not limited to, morpholinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide,and thiomorpholinyl. Further non-limiting exemplary cyclic moieties arethe following:

Also provided herein are compounds of Formula (XXIII), wherein whenR^(1′) is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocyclyl, heterocyclyloxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy,alkoxycarbonyl, or NR′R″, (wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety), wherein R^(1′) is optionallysubstituted with one or more of the following substituents: alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocyclyl,heterocyclyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl,alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety. Each of theabove substituents can be further substituted with one or moresubstituents chosen from alkyl, alkoxy, amido, amino, sulfonamido,acyloxy, alkoxycarbonyl, halo, cyano, hydroxyl, nitro, oxo, phosphate,urea, and carbonate.

For example, provided herein are compounds wherein when R^(1′) is alkyl,the alkyl is substituted with NR′R″ wherein R′ and R″ are taken togetherwith the nitrogen to form a cyclic moiety. The cyclic moiety so formedcan be unsubstituted or substituted. Non-limiting exemplary cyclicmoieties include, but are not limited to, morpholinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, and thiomorpholinyl. In otherexamples of the compounds of Formula (XXIII), when R^(1′) is alkyl, thealkyl is substituted with heterocyclyl, which includes, but is notlimited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolyl,tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of theabove listed heterocyclyl substituents can be unsubstituted orsubstituted.

In yet other examples of the compounds of Formula (XXIII), when R^(1′)is alkyl, the alkyl is substituted with a 5, 6, 7, 8, 9, or 10 memberedmonocyclic or bicyclic heteroaryl, which is unsubstituted orsubstituted. In some embodiments, the monocyclic heteroaryl includes,but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl,pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl,and oxazolyl. The bicyclic heteroaryl includes, but is not limited to,benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl,pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl,pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl,imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1, 2, 4]triazinyl.

In some embodiments of the compound of Formula (XXIII), L is —N(R²)—,wherein R² is hydrogen, unsubstituted or substituted C₁-C₁₀alkyl (whichincludes but is not limited to —CH₃, —CH₃CH₃, n-propyl, isopropyl,n-butyl, tent-butyl, sec-butyl, pentyl, hexyl, and heptyl), orunsubstituted or substituted C₃-C₇cycloalkyl (which includes but is notlimited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). Inother embodiments of the compound of Formula (XXIII), R² isunsubstituted or substituted heterocyclyl (which includes but is notlimited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, and piperazinyl), or unsubstituted or substitutedC₂-C₁₀heteroalkyl (which includes but is not limited to methoxyethoxy,methoxymethyl, and diethylaminoethyl). Alternatively, R² isunsubstituted or substituted monocyclic heteroaryl (which includes butis not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl,pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl,and oxazolyl) or unsubstituted or substituted monocyclic aryl.

In some embodiments of the compound of Formula (XXIII), R¹ is —OR^(1′),wherein R^(1′) is hydrogen or alkyl. In another example of the compoundof Formula (XXIII), R¹ is —O-alkyl, where alkyl is isopropyl.

In other embodiments of the compound of Formula (XXIII), R¹ is—NHR^(1′), —N(CH₃)R^(1′), —N(CH₂CH₃)R^(1′), —N(CH(CH₃)₂)R^(1′), or—OR^(1′), wherein R^(1′) is unsubstituted or substituted heterocyclyl(nonlimiting examples thereof include 4-NH piperidin-1-yl, 4-methylpiperidin-1-yl, 4-ethyl piperidin-1-yl, 4-isopropyl-piperidin-1-yl, andpyrrolidin-3-yl), unsubstituted or substituted monocyclic aryl, orunsubstituted or substituted monocyclic heteroaryl (including, but notlimited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl,pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, andoxazolyl.). In one example, R¹ is —O-aryl, i.e. phenoxy. In anotherexample, R¹ is —O-(4-methyl)piperidin-1-yl or—O-(4-isopropyl)piperidin-1-yl.

In some embodiments of compounds of Formula (XXIII), R¹′ is an amidogroup of the Formula

where R¹″ and R¹′″ are each independently hydrogen, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, or R¹″ and R¹′″ are taken together with nitrogen toform a cyclic moiety.

Also provided herein are compounds of Formula (XXIII), wherein whenR^(1′) is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocyclyl, heterocyclyloxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy,alkoxycarbonyl, or NR′R″ (wherein R′ and R″ are taken together withnitrogen to form a cyclic moiety), then R¹′ is optionally substitutedwith an amido group of the Formula:

where R¹″ and R¹′″ are each independently hydrogen, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, or R¹″ and R¹′″ are taken together with nitrogen toform a cyclic moiety.

When R¹″ and R¹′″ are taken together with the nitrogen to form a cyclicmoiety, the cyclic moiety can have, for example, from 3 to 8 ring atoms.The cyclic moiety so formed can further include one or more heteroatomswhich are selected from S, O, and N. In some embodiments, the cyclicmoiety so formed is unsubstituted or further substituted with a groupwhich is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxyl, nitro,phosphate, urea, or carbonate.

In some embodiments of the compound of Formula (XXIII), R¹ is one of thefollowing moieties:

In some embodiments of compounds of Formula (XXIII), the compound isselected from:

In some embodiments, the compound of Formula (XXIII) has the Formula(XXIV):

Alternatively, the compound has the Formula:

For example, the compound has the Formula (XXIIa):

In some embodiments of compounds of Formula (XXI), (XXII or (XXIIa),W_(d)is

and R¹² is hydrogen or halo. For example, W_(d) is

and R¹² is Cl—. In another instance, W_(d) is

and R¹² is hydrogen.

In other embodiments of compounds of Formula (XXI), (XXII or (XXIIa),W_(d) is

and R¹⁰ is hydrogen or halo.

In still other embodiments of compounds of Formula (XXI), (XXII or(XXIIa), W_(d) is

For example, W_(d) is

In some embodiments, the compound described herein is a compound ofFormula (XXI), (XXII or (XXIIa), where W_(b) ⁵ is N; X is —CH(R⁹)—,where R⁹ is methyl or ethyl; Y is —NH—; and W_(d) is

In some embodiments, W_(d) is

In other embodiments, W_(d) is

In yet other embodiments, W_(d) is

In some embodiments, W_(d) is

In one aspect, provided herein are compounds of Formula (XXV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein

W_(b) ¹ and W_(b) ² are each independently CR³, S, O, N or NR¹³, whereinat least one of W_(b) ¹ and W_(b) ² is CR³, N or NR¹³;

p is 0, 1, 2 or 3;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with0-4 occurrences of R²;

X is absent or is —(CH(R⁹))_(z)—;

Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—, —C(═O)—(CHR⁹)_(z)—,—C(═O)—, —N(R⁹)—C(═O)—, or —N(R⁹)—C(═O)NH—, —N(R⁹)C(R⁹)₂—, or—C(═O)—N(R⁹)—(CHR⁹)_(z);

each z is independently an integer of 1, 2, 3, or 4;

wherein when W_(b) ⁵ is N, no more than one of X or Y is absent;

each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate;

each R³ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl which isoptionally substituted with one or more R^(b), R¹¹ or R¹²;

wherein each R^(b) is independently hydrogen, halo, phosphate, urea,carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, amino, heteroalkyl, orheterocyclyl; and

each R¹¹ and R¹² is independently hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro,phosphate, urea, carboxylic acid, carbonate, or NR′R″, wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, W_(b) ⁵ is CR⁸. In some embodiments, R⁸ ishydrogen.

In certain embodiments, W_(b) ¹ is CR³. In some embodiments, W_(b) ¹ isN. In some embodiments, W_(b) ¹ is S. In some embodiments, W_(b) ¹ is O.

In certain embodiments, W_(b) ² is CR³. In some embodiments, W_(b) ² isN. In some embodiments, W_(b) ¹ is S. In some embodiments, W_(b) ¹ is O.

In some embodiments, W_(b) ¹ and W_(b) ² are CR³. In some embodiments,W_(b) ¹ is S and W_(b) ² is CR³. In some embodiments, W_(b) ¹ is S andW_(b) ² is N.

In certain embodiments, each R³ is independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide,sulfone, sulfonamido, halo, cyano, heteroaryl, aryl, hydroxyl, or nitro.In some embodiments, each R³ is independently hydrogen, alkyl,cycloalkyl, heterocyclyl, fluoroalkyl, alkoxy, halo, cyano, heteroarylor aryl. In some embodiments, R³ is hydrogen, alkyl, fluoroalkyl, alkoxyor aryl. In some embodiments, each R³ is hydrogen.

In certain embodiments, p is 0. In some embodiments, p is 1.

In certain embodiments, B is aryl (e.g., 6-membered aryl) substitutedwith 0-4 occurrences of R². In some embodiments, B is phenyl substitutedwith 0-4 occurrences of R². In some embodiments, B is phenyl substitutedwith 0 occurrences of R². In some embodiments, B is phenyl substitutedwith 1 occurrence of R². In some embodiments, R² is halo (e.g., fluoro).

In some embodiments, X is —(CH(R⁹))_(z)—. In some embodiments, z is 1.In some embodiments, R⁹ is C₁₋₁₀ alkyl (e.g., methyl).

In some embodiments, is absent, —O—, —NH(R⁹)—, or —S(═O)₂—. In certainembodiments, Y is absent. In some embodiments, Y is —N(R⁹)—. In someembodiments, R⁹ is hydrogen.

In certain embodiments, X—Y is

In some embodiments, X—Y is —CH₂—N(CH₃). In some embodiments, X—Y is(S)—CH(CH₃)—NH—. In some embodiments, X—Y is (R)—CH(CH₃)—NH—.

In some embodiments, W_(d) is aryl. In some embodiments, W_(d) isheteroaryl (e.g., a bicyclic heteroaryl). In some embodiments, W_(d) isselected from:

In some embodiments, W_(d) is

In other embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In certain embodiments, W_(d) is

In some embodiments, W_(d) is

In certain embodiments, W_(d) is

In certain embodiments, W_(d) is

In certain embodiments, W_(d) is

In certain embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In certain embodiments, R¹² is hydrogen, alkyl, alkoxy, hydroxyl,haloalkyl, halo, cyano, amino or amido. In some embodiments, R¹² ishydrogen. In some embodiments, R¹² is halo (e.g., chloro or fluoro). Insome embodiments, R¹² is cyano. In some embodiments, R¹² is amino. Insome embodiments, R¹² is amido (i.e., —C(═O)NH₂). In some embodiments,R¹² is alkyl (e.g., methyl). In some embodiments, R¹² is haloalkyl(e.g., trifluoromethyl). In some embodiments, R¹² is alkoxy (e.g.,methoxy). In some embodiments, R¹² is hydroxyl.

In certain embodiments, R¹¹ is hydrogen or amino. In some embodiments,R¹¹ is amino.

In certain embodiments, R^(b) is hydrogen or amino. In some embodiments,R^(b) is hydrogen. In some embodiments, R^(b) is amino.

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments. W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments, W_(d) is

In some embodiments of the compound of Formula (XXV), at least one ofR¹¹ and R¹² is hydrogen, cyano, halo, unsubstituted or substitutedalkyl, unsubstituted or substituted alkynyl, or unsubstituted orsubstituted alkenyl. In some embodiments, at least one of R¹¹ and R¹² isunsubstituted or substituted aryl. In some embodiments, at least one ofR¹¹ and R¹² is unsubstituted or substituted heteroaryl, which includes,but is not limited to, heteroaryl having a 5 membered ring, heteroarylhaving a six membered ring, heteroaryl with at least one nitrogen ringatom, heteroaryl with two nitrogen ring atoms, monocylic heteroaryl, andbicylic heteroaryl. In some embodiments, at least one of R¹ and R¹² isunsubstituted or substituted heterocyclyl, which includes, but is notlimited to, heterocyclyl with one nitrogen ring atom, heterocyclyl withone oxygen ring atom, heterocyclyl with one sulfur ring atom, 5 memberedheterocyclyl, 6 membered heterocyclyl, saturated heterocyclyl,unsaturated heterocyclyl, heterocyclyl having an unsaturated moietyconnected to the heterocyclyl ring, heterocyclyl substituted by oxo, andheterocyclyl substituted by two oxo. In some embodiments, at least oneof R¹¹ and R¹² is unsubstituted or substituted cycloalkyl, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloalkyl, each of which can be substituted by one oxo, and cycloalkylhaving an unsaturated moiety connected to the cycloalkyl ring. In someembodiments, at least one of R¹¹ and R¹² is unsubstituted or substitutedamido, unsubstituted or substituted acyloxy, unsubstituted orsubstituted alkoxycarbonyl, unsubstituted or substituted acyl, orunsubstituted or substituted sulfonamido.

In some embodiments, when at least one of R¹¹ and R¹² is alkyl, alkynyl,alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkoxycarbonyl,amido, acyloxy, acyl, or sulfonamido, it is substituted with one or moreof alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In certain embodiments, the compound of Formula (XXV) has a structure ofFormula (XXVI):

In some embodiments, the compound of Formula (XXVI) has a structure ofFormula (XXVIa) or (XXVIb):

In some embodiments, the compound of Formula (XXVI) has a structure ofFormula (XXVIIa) or (XXVIIb):

In some embodiments of compounds of Formula (XXVIa), (XXVIb), (XXVIIa),or (XXVIIb), B is aryl substituted with 0-3 occurrences of R². Forexample, B is phenyl substituted with 0-3 occurrences of R². In someembodiments of compounds of Formula (XXVIa), (XXVIb), (XXVIIa), or(XXVIIb), B is unsubstituted phenyl. In other embodiments of compoundsof Formula (XXVIa), (XXVIb), (XXVIIa), or (XXVIIb), B is phenylsubstituted with 1 occurrence of R². R² is, in some instances, halo oralkyl. In other embodiments of compounds of Formula (XXVIa), (XXVIb),(XXVIIa), or (XXVIIb), B is cycloalkyl or heterocyclyl.

In still other embodiments, the compound of Formula (I) has a structureselected from:

In certain embodiments, the compound of Formula (XXV) has a structure ofFormula (XXVIII):

In some embodiments, the compound of Formula (XXVIII) has a structure ofFormula (XXIX):

In certain embodiments, the compound of Formula (XXV) has a structure ofFormula (XXX):

In certain embodiments, the compound of Formula (XXX) has a structure ofFormula (XXXI):

In certain embodiments, the compound of Formula (XXX) has a structure ofFormula (XXXII):

In some embodiments, the compound of Formula (XXXII) has a structure ofFormula (XXXIII):

In another aspect, provided herein is a compound of Formula (XXXIV) or(XXXV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or their pharmaceutically acceptable formsthereof, wherein:

W_(b) ¹ and W_(b) ² are each independently CR³, S, O, N or NR¹³, whereinat least one of W_(b) ¹ and W_(b) ² is CR³, N or NR¹³;

p is 0, 1, 2 or 3;

W_(b) ⁵ is CR⁸, CHR⁸, or N;

R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl,or nitro;

R¹ is -(L)-R^(1′);

L is a bond, —S—, —N(R¹⁵)—, —C(═O)—, or —O—;

R^(1′) is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino,acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,nitro, phosphate, urea, carbonate, substituted nitrogen, or NR′R″wherein R′ and R″ are taken together with nitrogen to form a cyclicmoiety;

each R¹⁵ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl;

X is absent or is —(CH(R¹⁶))_(z);

Y is absent, —O—, —S—, —S(═O)₂—, —N(R¹⁶)—, —C(═O)—(CHR¹⁶)_(z)—, —C(═O)—,—N(R¹⁶)—C(═O)—, or —N(R¹⁶)—C(═O)NH—, —N(R¹⁶)C(R¹⁶)₂—, or—C(═O)—N(R¹⁶)—(CHR¹⁶)_(z)—;

each z is an integer of 1, 2, 3, or 4;

each R³ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,cyano, heteroaryl, aryl, hydroxyl, or nitro;

each R¹³ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl orheteroalkyl;

each R¹⁶ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,heteroalkyl, aryl, halo or heteroaryl;

W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl which isoptionally substituted with one or more R^(b), R¹¹ or R¹²;

wherein each R^(b) is independently hydrogen, halo, phosphate, urea,carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, amino, heteroalkyl, orheterocyclyl; and

each R¹¹ and R¹² is independently hydrogen, alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro,phosphate, urea, carboxylic acid, carbonate, or NR′R″, wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In certain embodiments, W_(b) ¹ is CR³ and W_(b) ² is CR³.

In certain embodiments, W_(b) ⁵ is CH.

In certain embodiments, L is a bond, —N(R¹⁵)— or —C(═O)—.

For all structures disclosed herein, the following embodiments apply totheir corresponding variable positions.

In some embodiments of the compounds disclosed herein, B is aryl orheteroaryl substituted with 0 or 1 occurrences of R² and Cy is a 5- or6-membered aryl or heteroaryl group. For example, B is aryl substitutedwith 0 or 1 occurrences of R² and Cy is a 5- or 6-membered aryl orheteroaryl group. In another example, B is aryl or heteroarylsubstituted with 0 or 1 occurrence of R² and Cy is a 6-membered arylgroup. Cy is, for instance, phenyl substituted with alkyl, fluoroalkyl,aryl, heteroaryl or halo.

In other embodiments of the compounds disclosed herein, B is aryl orheteroaryl substituted with 0 or 1 occurrences of R², Cy is a 5- or6-membered aryl or heteroaryl group, X is —(CH(R⁹))_(z)— and Y is—NH(R⁹)—, wherein each R⁹ is chosen independently from hydrogen, alkyl,cycloalkyl, and heteroalkyl. For example, X—Y is —CH₂(CH₃)—NH—. In someembodiments, B is aryl substituted with 0 or 1 occurrences of R² and Cyis a 5- or 6-membered aryl or heteroaryl group. In another example, B isaryl or heteroaryl substituted with 0 or 1 occurrence of R² and Cy is a6-membered aryl group. Cy is, for instance, phenyl substituted withalkyl, fluoroalkyl, aryl, heteroaryl or halo.

In some embodiments, B is cycloalkyl, heterocyclyl, aryl, or heteroaryl,which is substituted with 0-4 occurrences of R², R³ is H, halo, alkyl,alkoxy, aryl, cycloalkyl, or heteroaryl, each R⁵ is H, halo, alkyl,alkoxy, aryl, cycloalkyl, or heteroaryl, and R⁹ is hydrogen or alkyl.

In some embodiments, B is unsubstituted or substituted alkyl, including,but not limited to, —(CH₂)₂—NR^(a)R^(a), wherein each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, or NR^(a)R^(a) are combined together to form a cyclicmoiety, which includes but is not limited to piperidinyl, piperazinyl,and morpholinyl. In some embodiments, B is unsubstituted or substitutedamino. In some embodiments, B is unsubstituted or substitutedheteroalkyl.

In some embodiments, B is selected from unsubstituted or substitutedaryl, including, but not limited to, unsubstituted or substitutedphenyl; unsubstituted or substituted heteroaryl including, but notlimited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl,pyrimidin-2-yl, pyrimidin-5-yl, or pyrazin-2-yl, unsubstituted orsubstituted monocyclic heteroaryl, unsubstituted or substituted bicyclicheteroaryl, heteroaryl having two heteroatoms as ring atoms,unsubstituted or substituted heteroaryl comprising a nitrogen ring atom,heteroaryl comprising two nitrogen ring atoms, heteroaryl having anitrogen and a sulfur as ring atoms, unsubstituted or substitutedheterocyclyl including, but not limited to, morpholinyl,tetrahydropyranyl, piperazinyl, and piperidinyl, unsubstituted orsubstituted cycloalkyl including, but not limited to, cyclopentyl andcyclohexyl.

In some embodiments, B is unsubstituted or substituted with one or moreR² substituents. In some embodiments, R² is alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxylor nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, or sulfonamido, can itself be substituted.

In some embodiments, R² is unsubstituted or substituted alkyl,unsubstituted or substituted heteroalkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted cycloalkyl, or unsubstituted or substituted heterocyclyl. Insome embodiments, R² is unsubstituted or substituted aryl, unsubstitutedor substituted arylalkyl, unsubstituted or substituted heteroaryl, orunsubstituted or substituted heteroarylalkyl. In some embodiments, R² isunsubstituted or substituted alkoxy, unsubstituted or substituted amido,unsubstituted or substituted amino. In some embodiments, R² isunsubstituted or substituted acyl, unsubstituted or substituted acyloxy,unsubstituted or substituted alkoxycarbonyl, or unsubstituted orsubstituted sulfonamido. In some embodiments, R² is halo, selected from—I, —F, —Cl, or —Br. In some embodiments, R² is selected from cyano,hydroxyl, nitro and a carbonate. In some embodiments, R² isunsubstituted or substituted phosphate. In some embodiments, R² isunsubstituted or substituted urea. In some embodiments, when R² isalkyl, R² is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, pentyl, hexyl or heptyl.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynylcycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, orhydroxyl, it is substituted by phosphate, substituted by urea, orsubstituted by carbonate.

In some embodiments, when R² is alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, itis substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl or nitro,each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,alkoxycarbonyl, or sulfonamido can itself be substituted.

In some embodiments, there are no occurrences of R². In otherembodiments, there is one occurrence of R². In still other embodiments,there are two occurrences of R². In yet other embodiments, there arethree occurrences of R². In yet other embodiments, there are fouroccurrences of R². For example, in some embodiments B is aryl orheteroaryl and there are no occurrences of R². In other instances, B isaryl or heteroaryl and there is one occurrence of R² where R² is alkylor halo.

In some embodiments, R³ is halo, alkyl, alkoxy, heteroaryl, orcycloalkyl. For example, R³ is H, CH₃, CH₃CH₃, CF₃, Cl, or F. In otherembodiments, R³ is CH₃, CF₃, or Cl. In other embodiments, each R³ and R⁸is independently selected from H, CH₃, OCH₃, CF₃, and halo.

In some embodiments, R³ is unsubstituted or substituted alkyl,unsubstituted or substituted alkenyl, or unsubstituted or substitutedalkynyl. In some embodiments, R³ is unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedcycloalkyl, or unsubstituted or substituted heterocyclyl. In someembodiments, R³ is unsubstituted or substituted alkoxy, unsubstituted orsubstituted amido, unsubstituted or substituted amino. In someembodiments, R³ is unsubstituted or substituted acyl, unsubstituted orsubstituted acyloxy, unsubstituted or substituted alkoxycarbonyl, orunsubstituted or substituted sulfonamido. In some embodiments, R³ ishalo, selected from —I, —F, —Cl, or —Br. In some embodiments, R³ ishalo, alkyl, alkoxy, heteroaryl, or cycloalkyl. For example, R³ is CH₃,CH₂CH₃, CF₃, Cl, or F. In some instances, R³ is CH₃, CF₃, or Cl.

In some embodiments, R³ is selected from cyano, hydroxyl, and nitro. Insome embodiments, when R³ is alkyl, R³ is methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl or heptyl. Insome embodiments, R³ is —CF₃, —CH₂F or —CHF₂.

In some embodiments, when R³ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclyl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, or sulfonamido, it is substituted with one ormore of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In some embodiments, R³ is a 5-membered heteroaryl group. Such groupsinclude, for example, pyrrole, furan, thiophene, triazole, oxazole,pyrazole, and isoxazole. In other embodiments, R³ is a 5-memberednonaromatic heterocycle, including, but not limited to, oxazoline andoxazolidinone. In still other embodiments, R³ is a 6-membered heteroarylgroup including pyridine, pyrazine, pyrimidine and pyridazine.Alternatively, R³ is a 6-membered nonaromatic heterocycle, includingmoieties such as morpholino or piperidino. In other embodiments, R³ is afused 5/6-bicyclic heteroaryl, for example benzothiazole, benzoxazole,benzisoxazole, indazole, benzimidazole, benzothiophene, indole,isoindole, purine, or pyrazolopyrimidine. In yet other embodiments, R³is a fused 5/6-bicyclic nonaromatic heterocycle.

In some embodiments, R³ is a C₁-C₆ alkyl group substituted with a5-membered heteroaryl, a 5-membered heterocycle, a 6-memberedheteroaryl, a 6-membered nonaromatic heterocycle, a fused 5/6-bicyclicheteroaryl, or a fused 5/6-bicyclic nonaromatic heterocycle.Alternatively, R³ is amino, sulfinyl, sulfonyl, sulfoxide, sulfone, oralkoxy wherein the N, S, and O heteroatom has a covalent bond eitherdirectly or through a C₁-C₆ alkyl group to a 5-membered heteroaryl, a5-membered nonaromatic heterocycle, a 6-membered heteroaryl, a6-membered heterocycle, a fused 5/6-bicyclic heteroaryl, or a fused5/6-bicyclic heterocycle.

In other embodiments, R³ is a C₁-C₆ alkyl group substituted with a fusedpolycyclic group, wherein the polycyclic group has greater than tworings and is carbocyclic or heterocyclic; C₁-C₆ alkyl group substitutedwith a bridged cycloalkyl or bridged heterocyclic group; C₁-C₆ alkylgroup substituted with a spirocyclic cycloalkyl or spirocyclicheterocyclic group; or branched C₄-C₁₂ alkyl group, wherein saidbranched alkyl group contains at least one terminal t-butyl group.

Each of the embodiments named above for R³ is unsubstituted oroptionally additionally substituted with an alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxylor nitro group.

In certain embodiments, R³ is a substituted or unsubstitutedheterocyclyl or heteroaryl group selected from pyridine, pyrazole,piperazine, and pyrrolidine, wherein the substituent can be a C₁-C₆alkyl group or a halogen.

In some embodiments, a compound is provided wherein R³ is selected froma 5-membered heteroaryl such as pyrrole, a furan, and a thiophene group;5-membered heterocycle such as pyrrolidine, a tetrahydrofuran, or atetrahydrothiophene group; 6-membered heteroaryl such as pyridine,pyrazine, pyrimidine, and pyridazine; 6-membered heterocycle such aspiperidine, tetrahydropyran, and thiane; and fused 5/6-bicyclicheteroaryl such as indole, isoindole, benzofuran, isobenzofuran,benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, andpurine. In certain embodiments, R³ is a substituted or unsubstitutedgroup selected from pyridine, pyrazole, piperazine, and pyrrolidine. Byway of non-limiting example, the R³ group can be substituted with aC₁-C₆ alkyl group or a halogen. For example, the R³ group can besubstituted with a methyl group.

In some embodiments, a compound is provided wherein R³ is selected from

wherein R is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo and haloalkyl. Incertain embodiments, R is methyl. In other embodiments, a compound isprovided wherein R³ is selected from:

In some embodiments, each R⁵ is independently unsubstituted orsubstituted alkyl (including, but not limited to, unsubstituted orsubstituted C₁-C₄alkyl). In some embodiments, each R⁵ is independentlyunsubstituted or substituted alkenyl including, but not limited to,unsubstituted or substituted C₂-C₅alkenyl. In some embodiments, each R⁵is independently unsubstituted or substituted alkynyl including, but notlimited to, unsubstituted or substituted C₂-C₅alkynyl. In someembodiments, each R⁵ is independently unsubstituted or substitutedcycloalkyl including, but not limited to, unsubstituted or substitutedC₃-C₅cycloalkyl. In some embodiments, each R⁵ is independentlyunsubstituted or substituted heterocyclyl. In some embodiments, each R⁵is independently unsubstituted or substituted heteroalkyl including, butnot limited to, unsubstituted or substituted C_(r) C₄heteroalkyl. Insome embodiments, each R⁵ is independently unsubstituted or substitutedalkoxy including, but not limited to, unsubstituted or substitutedC₁-C₄alkoxy. In some embodiments, each R⁵ is independently unsubstitutedor substituted amido including, but not limited to, unsubstituted orsubstituted C₁-C₄amido. In some embodiments, each R⁵ is independentlyunsubstituted or substituted amino. In some embodiments, each R⁵ isindependently unsubstituted or substituted acyl, unsubstituted orsubstituted acyloxy, unsubstituted or substituted C₁-C₄acyloxy,unsubstituted or substituted alkoxycarbonyl, unsubstituted orsubstituted sulfonamido, or unsubstituted or substitutedC₁-C₄sulfonamido. In some embodiments, each R⁵ is independently halo,selected from —I, —F, —Cl, and —Br. In some embodiments, each R⁵ isindependently selected from cyano, hydroxyl, and nitro. In some otherembodiments, each R⁵ is independently —CH₃, —CH₂CH₃, n-propyl,isopropyl, —OCH₃, —OCH₂CH₃, or —CF₃.

In some embodiments, when R⁵ is alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, orsulfonamido, R³ is independently optionally substituted with one or moreof alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl or nitro, each of which alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, orsulfonamido can itself be substituted.

In some embodiments, no R⁵ moieties are present.

In some embodiments, X is absent. In some embodiments, X is—(CH(R⁹))_(z)—, and z is an integer of 1, 2, 3 or 4.

In some embodiments, R⁹ is unsubstituted or substituted alkyl including,but not limited to, unsubstituted or substituted C₁-C₁₀alkyl. In someembodiments, R⁹ is unsubstituted or substituted cycloalkyl including,but not limited to, unsubstituted or substituted C₃-C₇cycloalkyl. Insome embodiments, R⁹ is ethyl, methyl or hydrogen. In some embodiments,R⁹ is unsubstituted or substituted heterocyclyl including, but notlimited to, unsubstituted or substituted C₇-C₁₀heteroalkyl. In someembodiments, R⁹ is unsubstituted or substituted heteroalkyl including,but not limited to, unsubstituted or substituted C₂-C₁₀heteroalkyl.

Also provided herein are compounds wherein R⁹ is hydrogen, and X is—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)—, or —CH(CH₂CH₃)—. In otherembodiments, X is —(CH(R⁹))_(z)—, R⁹ is not hydrogen, and z is aninteger of 1. When X is —CH(R⁹)— and R⁹ is not hydrogen, then thecompound can adopt either an (S)- or (R)-stereochemical configurationwith respect to the CH carbon. In some embodiments, the compound is aracemic mixture of (S)- and (R) isomers with respect to the CH carbon.In other embodiments, provided herein is a mixture of a given disclosedcompound wherein individual compounds of the mixture exist predominatelyin an (S)- or (R)-isomeric configuration. For example, the compoundmixture has an (S)-enantiomeric excess of greater than about 55%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, ormore at the X carbon. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericexcess of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5%, or more at the X carbon. In someother embodiments, the compound mixture has an (R)-enantiomeric excessof greater than about 55% to about 99.5%, greater than about 60% toabout 99.5%, greater than about 65% to about 99.5%, greater than about70% to about 99.5%, greater than about 75% to about 99.5%, greater thanabout 80% to about 99.5%, greater than about 85% to about 99.5%, greaterthan about 90% to about 99.5%, greater than about 95% to about 99.5%,greater than about 96% to about 99.5%, greater than about 97% to about99.5%, greater than about 98% to greater than about 99.5%, greater thanabout 99% to about 99.5%, or more.

In some embodiments of the compounds disclosed herein, X is —CH(R⁹)—, R⁹is methyl or ethyl, and the compound is the (S)-isomer.

In some embodiments of the compounds disclosed herein, Y is absent.

In some embodiments, Y is —O—, —S—, —S(═O)—, —C(═O)—, —N(R⁹)(C═O)—,—N(R⁹)(C═O)NH—, —N(R⁹)C(R⁹)₂— (such as —N(R⁹)CH₂—, including, but notlimited to, —N(CH₃)CH₂—, N(CH(CH₃)₂)CH₂— or N(CH₂CH₃)CH₂—), —N(R⁹)—,—N(CH₃)—, —N(CH₂CH₃)—, or —N(CH(CH₃)₂)—. In some embodiments, Y is—C(═O)—(CHR⁹)_(z)— and z is an integer of 1, 2, 3, or 4.

In some embodiments, at least one of X and Y is present. In someembodiments of the compounds disclosed herein, —XY— is —CH₂—,—CH₂—N(CH₃), —CH₂—N(CH₂CH₃), —CH(CH₃)—NH—, (S)—CH(CH₃)—NH—, or(R)—CH(CH₃)—NH—. In other embodiments, X—Y is —N(CH₃)—CH₂—,N(CH₂CH₃)CH₂—, —N(CH(CH₃)₂)CH₂—, or —NHCH₂—.

In some embodiments, B is one of the following moieties:

In one aspect, B is selected from the moieties presented in Table 1.

TABLE 1 Illustrative B moieties of the compounds described herein.Sub-class # B B-1

B-2

B-3 —CH(CH₃)₂ B-4

B-5

B-6

B-7

B-8

B-9

B-10

B-11

B-12

B-13

B-14

B-15

B-16

B-17

B-18

B-19

B-20

B-21

B-22

B-23

B-24

B-25

B-26

B-27

B-28

B-29

B-30

B-31

B-32

B-33

B-34

B-35

B-36

B-37

B-38

B-39

B-40

B-41

B-42

B-43

B-44

B-45

B-46

B-47

B-48

B-49

B-50

B-51

B-52

B-53

B-54

B-55

B-56

B-57

B-58

B-59

B-60

B-61

B-62

B-63

B-64

B-65

B-66

B-67

B-68

B-69

B-70

B-71

B-72

B-73

B-74

B-75

B-76

B-77

B-78

B-79

B-80

B-81

B-82

B-83

B-84

B-85

B-86

B-87 —CH₃ B-88 —CH₂CH₃ B-89

B-90

B-91

B-92

B-93

B-94

B-95

B-96

B-97

B-98

B-99

B-100

B-101

B-102

In some embodiments, one or more compounds described herein bind to aPI3 kinase (e.g., bind selectively). In some embodiments, one or morecompounds described herein bind selectively to a γ or δ subtype of a PI3kinase.

In some embodiments, the IC₅₀ of a subject compound for p110α, p110β,p110γ, or p110δ is less than about 1 μM, less than about 100 nM, lessthan about 50 nM, less than about 10 nM, less than 1 nM or even lessthan about 0.5 nM. In some embodiments, the IC₅₀ of a subject compoundfor mTor is less than about 1 μM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than 1 nM or even less thanabout 0.5 nM. In some other embodiments, one or more subject compoundsexhibit dual binding specificity and are capable of inhibiting a PI3kinase (e.g., a class I PI3 kinase) as well as a protein kinase (e.g,mTor) with an IC₅₀ value less than about 1 μM, less than about 100 nM,less than about 50 nM, less than about 10 nM, less than 1 nM or evenless than about 0.5 nM. One or more subject compounds are capable ofinhibiting tyrosine kinases including, for example, DNA-dependentprotein kinase (Pubmed protein accession number (PPAN) AAA79184), Abltyrosine kinase (CAA52387), Bcr-Abl, hemopoietic cell kinase (PPANCAI19695), Src (PPAN CAA24495), vascular endothelial growth factorreceptor 2 (PPAN ABB82619), vascular endothelial growth factorreceptor-2 (PPAN ABB82619), epidermal growth factor receptor (PPANAG43241), EPH receptor B4 (PPAN EAL23820), stem cell factor receptor(PPAN AAF22141), Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858),fms-related tyrosine kinase 3 (PPAN NP_(—)004110), platelet-derivedgrowth factor receptor alpha (PPAN NP_(—)990080), RET (PPAN CAA73131),and functional mutants thereof. In some embodiments, the tyrosine kinaseis Abl, Bcr-Abl, EGFR, or Flt-3, and any other kinases listed in theTables herein.

In some embodiments, non-limiting exemplary compounds exhibit one ormore functional characteristics disclosed herein. For example, one ormore subject compounds bind specifically to a PI3 kinase. In someembodiments, the IC₅₀ of a subject compound for p110α, p110β, p110γ, orp110δ is less than about 1 μM, less than about 100 nM, less than about50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5nM, less than about 100 pM, or less than about 50 pM.

In some embodiments, one or more of the subject compounds canselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC₅₀ value of about100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measuredin an in vitro kinase assay.

In some embodiments, one or more of the subject compounds canselectively inhibit one or two members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) such as PI3-kinase α,PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some aspects, some ofthe subject compounds selectively inhibit PI3-kinase δ as compared toall other type I PI3-kinases. In other aspects, some of the subjectcompounds selectively inhibit PI3-kinase δ and PI3-kinase γ as comparedto the rest of the type I PI3-kinases. In yet other aspects, some of thesubject compounds selectively inhibit PI3-kinase α and PI3-kinase β ascompared to the rest of the type I PI3-kinases. In still yet some otheraspects, some of the subject compounds selectively inhibit PI3-kinase δand PI3-kinase α as compared to the rest of the type I PI3-kinases. Instill yet some other aspects, some of the subject compounds selectivelyinhibit PI3-kinase δ and PI3-kinase β as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase αas compared to the rest of the type I PI3-kinases, or selectivelyinhibit PI3-kinase α and PI3-kinase γ as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase βas compared to the rest of the type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC₅₀) with respect to a given type IPI3-kinase, that is at least about 10-fold, at least about 20-fold, atleast about 50-fold, at least about 100-fold, at least about 1000-fold,at least about 10,000-fold, or lower, than the inhibitor's IC₅₀ withrespect to the rest of the other type I PI3-kinases. In one embodiment,an inhibitor selectively inhibits PI3-kinase as compared to PI3-kinase βwith at least about 10-fold lower IC₅₀ for PI3-kinase δ. In certainembodiments, the IC₅₀ for PI3-kinase δ is below about 100 nM, while theIC₅₀ for PI3-kinase β is above about 1000 nM. In certain embodiments,the IC₅₀ for PI3-kinase δ is below about 50 nM, while the IC₅₀ forPI3-kinase β is above about 5000 nM. In certain embodiments, the IC₅₀for PI3-kinase δ is below about 10 nM, while the IC₅₀ for PI3-kinase βis above about 1000 nM, above about 5,000 nM, or above about 10,000 nM.

Pharmaceutical Compositions

In some embodiments, provided herein are pharmaceutical compositionscomprising one or more compounds as disclosed herein, or apharmaceutically acceptable form thereof (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives), and one or more pharmaceuticallyacceptable excipients carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Insome embodiments, a pharmaceutical composition described herein includesa second active agent such as an additional therapeutic agent, (e.g., achemotherapeutic).

1. Formulations

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid for n, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can beemployed in pharmaceutical compositions include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol, and the like),and suitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form can be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound described herein and/or thechemotherapeutic with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound as disclosed herein withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety. Exceptinsofar as any conventional excipient medium is incompatible with thecompounds provided herein, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutically acceptable composition,the excipient's use is contemplated to be within the scope of thisdisclosure.

In some embodiments, the concentration of one or more of the compoundsprovided in the disclosed pharmaceutical compositions is less than about100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%,about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%,about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%,about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is greater than about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%,about 19.50%, about 19.25% about 19%, about 18.75%, about 18.50%, about18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%,about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%,about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%,about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%,about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%,about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%,about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%,about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% w/w, w/v,or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.0001% toapproximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%,approximately 1% to approximately 10% w/w, w/v or v/v, v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is equal to or less than about 10 g, about 9.5 g, about9.0 g, about 8.5 g, about 8.0 g, 7.5 g, about 7.0 g, about 6.5 g, about6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g,about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g,about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g,about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about0.0001 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is more than about 0.0001 g, about 0.0002 g, about0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g. about 0.004 g,about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g,about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g,about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g,about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g,about 2.5, about 3 g, about 3.5, about 4 g, about 4.5 g, about 5 g,about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g,about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is in the range of about 0.0001-about 10 g, about0.0005-about 9 g, about 0.001-about 8 g, about 0.005-about 7 g, about0.01-about 6 g, about 0.05-about 5 g, about 0.1-about 4 g, about0.5-about 4 g, or about 1-about 3 g.

1A. Formulations for Oral Administration

In some embodiments, provided herein are pharmaceutical compositions fororal administration containing a compound as disclosed herein, and apharmaceutical excipient suitable for oral administration. In someembodiments, provided herein are pharmaceutical compositions for oraladministration containing: (i) an effective amount of a disclosedcompound; optionally (ii) an effective amount of one or more secondagents; and (iii) one or more pharmaceutical excipients suitable fororal administration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more ingredients. In general, the pharmaceuticalcompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the pharmaceutical compositions for an oral dosage form, anyof the usual pharmaceutical media can be employed as carriers, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with the solid oralpreparations. In some embodiments, tablets can be coated by standardaqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants can be used in the pharmaceutical compositions as providedherein to provide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant can produce tablets which candisintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration, and can be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, canbe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein can be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, forexample, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of atleast about 10, while suitable lipophilic surfactants can generally havean HLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants can be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants can include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids, and sterols; polyoxyethylene sterols, derivatives, and analoguesthereof; polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate. PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids and sterols; oil-soluble vitamins/vitamin derivatives; andmixtures thereof. Within this group, non-limiting examples of lipophilicsurfactants include glycerol fatty acid esters, propylene glycol fattyacid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member ofvegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound as provided herein and to minimize precipitation of thecompound. This can be especially important for pharmaceuticalcompositions for non-oral use, e.g., pharmaceutical compositions forinjection. A solubilizer can also be added to increase the solubility ofthe hydrophilic drug and/or other components, such as surfactants, or tomaintain the pharmaceutical composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In someembodiments, solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer can be limited to abioacceptable amount, which can be readily determined by one of skill inthe art. In some circumstances, it can be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the pharmaceutical composition toa subject using conventional techniques, such as distillation orevaporation. Thus, if present, the solubilizer can be in a weight ratioof about 10%, 25%, 50%, 100%, or up to about 200% by weight, based onthe combined weight of the drug, and other excipients. If desired, verysmall amounts of solubilizer can also be used, such as about 5%, 2%, 1%or even less. Typically, the solubilizer can be present in an amount ofabout 1% to about 100%, more typically about 5% to about 25% by weight.

The pharmaceutical composition can further include one or morepharmaceutically acceptable additives and excipients. Such additives andexcipients include, without limitation, detackifiers, anti-foamingagents, buffering agents, polymers, antioxidants, preservatives,chelating agents, viscomodulators, tonicifiers, flavorants, colorants,oils, odorants, opacifiers, suspending agents, binders, fillers,plasticizers, lubricants, and mixtures thereof.

Exemplary preservatives can include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. Exemplaryantioxidants include, but are not limited to, alpha tocopherol, ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, monothioglycerol, potassium metabisulfite, propionicacid, propyl gallate, sodium ascorbate, sodium bisulfite, sodiummetabisulfite, and sodium sulfite. Exemplary chelating agents includeethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid, and trisodiumedetate. Exemplary antimicrobial preservatives include, but are notlimited to, benzalkonium chloride, benzethonium chloride, benzylalcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.Exemplary antifungal preservatives include, but are not limited to,butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoicacid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, and sorbic acid. Exemplary alcoholpreservatives include, but are not limited to, ethanol, polyethyleneglycol, phenol, phenolic compounds, bisphenol, chlorobutanol,hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid. Other preservatives include, but arenot limited to, tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES), sodium bisulfite, sodium metabisulfite, potassiumsulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben,Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certainembodiments, the preservative is an anti-oxidant. In other embodiments,the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof.

In addition, an acid or a base can be incorporated into thepharmaceutical composition to facilitate processing, to enhancestability, or for other reasons. Examples of pharmaceutically acceptablebases include amino acids, amino acid esters, ammonium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesiumaluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite,magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine,trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.Also suitable are bases that are salts of a pharmaceutically acceptableacid, such as acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonicacid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearicacid, succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid, uric acid, and the like. Salts of polyproticacids, such as sodium phosphate, disodium hydrogen phosphate, and sodiumdihydrogen phosphate can also be used. When the base is a salt, thecation can be any convenient and pharmaceutically acceptable cation,such as ammonium, alkali metals, alkaline earth metals, and the like.Examples can include, but not limited to, sodium, potassium, lithium,magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

1B. Formulations for Parenteral Administration

In some embodiments, provided herein are pharmaceutical compositions forparenteral administration containing a compound as disclosed herein, anda pharmaceutical excipient suitable for parenteral administration. Insome embodiments, provided herein are pharmaceutical compositions forparenteral administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor parenteral administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

The forms in which the disclosed pharmaceutical compositions can beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound asdisclosed herein in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as appropriate, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the appropriateother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation are vacuum-drying and freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionalingredient from a previously sterile-filtered solution thereof.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. Injectable compositions can contain from about 0.1to about 5% w/w of a compound as disclosed herein.

1C. Formulations for Topical Administration

In some embodiments, provided herein are pharmaceutical compositions fortopical (e.g., transdermal) administration containing a compound asdisclosed herein, and a pharmaceutical excipient suitable for topicaladministration. In some embodiments, provided herein are pharmaceuticalcompositions for topical administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for topical administration. In some embodiments, thepharmaceutical composition further contains: (iv) an effective amount ofa third agent.

Pharmaceutical compositions provided herein can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationcan provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the disclosed methods employstransdermal delivery devices (“patches”). Such transdermal patches canbe used to provide continuous or discontinuous infusion of a compound asprovided herein in controlled amounts, either with or without anotheragent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquid jet injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) compound of formula (I), although theconcentration of the compound of formula (I) can be as high as thesolubility limit of the compound of formula (I) in the solvent. In someembodiments, topically-administrable formulations can, for example,comprise from about 1% to about 9% (w/w) compound of formula (I), suchas from about 1% to about 8% (w/w), further such as from about 1% toabout 7% (w/w), further such as from about 1% to about 6% (w/w), furthersuch as from about 1% to about 5% (w/w), further such as from about 1%to about 4% (w/w), further such as from about 1% to about 3% (w/w), andfurther such as from about 1% to about 2% (w/w) compound of formula (I).Formulations for topical administration can further comprise one or moreof the additional pharmaceutically acceptable excipients describedherein.

1D. Formulations for Inhalation Administration

In some embodiments, provided herein are pharmaceutical compositions forinhalation administration containing a compound as disclosed herein, anda pharmaceutical excipient suitable for topical administration. In someembodiments, provided herein are pharmaceutical compositions forinhalation administration containing: (i) an effective amount of adisclosed compound; optionally (ii) an effective amount of one or moresecond agents; and (iii) one or more pharmaceutical excipients suitablefor inhalation administration. In some embodiments, the pharmaceuticalcomposition further contains: (iv) an effective amount of a third agent.

Pharmaceutical compositions for inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof and powders. The liquid or solidpharmaceutical compositions can contain suitable pharmaceuticallyacceptable excipients as described herein. In some embodiments, thepharmaceutical compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Pharmaceuticalcompositions in pharmaceutically acceptable solvents can be nebulized byuse of inert gases. Nebulized solutions can be inhaled directly from thenebulizing device or the nebulizing device can be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder pharmaceutical compositions can beadministered, e.g., orally or nasally, from devices that deliver theformulation in an appropriate manner.

1E. Formulations for Ocular Administration

In some embodiments, the disclosure provides a pharmaceuticalcomposition for treating ophthalmic disorders. The pharmaceuticalcomposition can contain an effective amount of a compound as disclosedherein and a pharmaceutical excipient suitable for ocularadministration. Pharmaceutical compositions suitable for ocularadministration can be presented as discrete dosage forms, such as dropsor sprays each containing a predetermined amount of an active ingredienta solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Otheradministration forms include intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds as disclosed herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye can be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration can be feasible including, but notlimited to, intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in asterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles can be chosen, as is known in the art,including, but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. In some embodiments,additives ordinarily used in the eye drops can be added. Such additivesinclude isotonizing agents (e.g., sodium chloride, etc.), buffer agent(e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogenphosphate, etc.), preservatives (e.g., benzalkonium chloride,benzethonium chloride, chlorobutanol, etc.), thickeners (e.g.,saccharide such as lactose, mannitol, maltose, etc.; e.g., hyaluronicacid or its salt such as sodium hyaluronate, potassium hyaluronate,etc.; e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g.,sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents known to those skilled in theart).

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quarternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases, the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, rnyristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

1F. Formulations for Controlled Release Administration

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a compound as disclosedherein, and a pharmaceutical excipient suitable for controlled releaseadministration. In some embodiments, provided herein are pharmaceuticalcompositions for controlled release administration containing: (i) aneffective amount of a disclosed compound; optionally (ii) an effectiveamount of one or more second agents; and (iii) one or morepharmaceutical excipients suitable for controlled releaseadministration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

Active agents such as the compounds provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970;6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each ofwhich is incorporated herein by reference. Such dosage forms can be usedto provide slow or controlled release of one or more active agentsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. Thus, the pharmaceuticalcompositions provided encompass single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the disease, disorder, orcondition in a minimum amount of time. Advantages of controlled releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased subject compliance. In addition, controlledrelease formulations can be used to affect the time of onset of actionor other characteristics, such as blood levels of the drug, and can thusaffect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound as disclosed herein thatpromptly produces the desired therapeutic effect, and gradually andcontinually release other amounts of the compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In order to maintain this constant level of the compound in the body,the compound should be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active agent can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used. In yet another embodiment, a controlled releasesystem can be placed in a subject at an appropriate site determined by apractitioner of skill, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

2. Dosage

A compound described herein can be delivered in the form ofpharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds describedherein and/or one or more additional therapeutic agents such as achemotherapeutic, formulated together with one or more pharmaceuticallyacceptable excipients. In some instances, the compound described hereinand the additional therapeutic agent are administered in separatepharmaceutical compositions and can (e.g., because of different physicaland/or chemical characteristics) be administered by different routes(e.g., one therapeutic is administered orally, while the other isadministered intravenously). In other instances, the compound describedherein and the additional therapeutic agent can be administeredseparately, but via the same route (e.g., both orally or bothintravenously). In still other instances, the compound described hereinand the additional therapeutic agent can be administered in the samepharmaceutical composition.

The selected dosage level will depend upon a variety of factorsincluding, for example, the activity of the particular compoundemployed, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

In general, a suitable daily dose of a compound described herein and/ora chemotherapeutic will be that amount of the compound which, in someembodiments, can be the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above. Generally, doses of the compounds described herein fora patient, when used for the indicated effects, will range from about0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg perday, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about100 mg per day, or about 0.0001 mg to about 500 mg per day, or about0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg perday, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg. Anexemplary dosage is about 10 to 30 mg per day. In some embodiments, fora 70 kg human, a suitable dose would be about 0.05 to about 7 g/day,such as about 0.05 to about 2.5 g/day. Actual dosage levels of theactive ingredients in the pharmaceutical compositions described hereincan be varied so as to obtain an amount of the active ingredient whichis effective to achieve the desired therapeutic response for aparticular patient, composition, and mode of administration, withoutbeing toxic to the patient. In some instances, dosage levels below thelower limit of the aforesaid range can be more than adequate, while inother cases still larger doses can be employed without causing anyharmful side effect, e.g., by dividing such larger doses into severalsmall doses for administration throughout the day.

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, or bi-weekly. Thedosing schedule can include a “drug holiday,” i.e., the drug can beadministered for two weeks on, one week off, or three weeks on, one weekoff, or four weeks on, one week off, etc., or continuously, without adrug holiday. The compounds can be administered orally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intranasally, sublingually, or by any other route.

In some embodiments, a compound as provided herein is administered inmultiple doses. Dosing can be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing canbe about once a month, about once every two weeks, about once a week, orabout once every other day. In another embodiment, a compound asdisclosed herein and another agent are administered together about onceper day to about 6 times per day. In another embodiment, theadministration of a compound as provided herein and an agent continuesfor less than about 7 days. In yet another embodiment, theadministration continues for more than about 6, about 10, about 14,about 28 days, about two months, about six months, or about one year. Insome cases, continuous dosing is achieved and maintained as long asnecessary.

Administration of the pharmaceutical compositions as disclosed hereincan continue as long as necessary. In some embodiments, an agent asdisclosed herein is administered for more than about 1, about 2, about3, about 4, about 5, about 6, about 7, about 14, or about 28 days. Insome embodiments, an agent as disclosed herein is administered for lessthan about 28, about 14, about 7, about 6, about 5, about 4, about 3,about 2, or about 1 day. In some embodiments, an agent as disclosedherein is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

Since the compounds described herein can be administered in combinationwith other treatments (such as additional chemotherapeutics, radiationor surgery), the doses of each agent or therapy can be lower than thecorresponding dose for single-agent therapy. The dose for single-agenttherapy can range from, for example, about 0.0001 to about 200 mg, orabout 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1to about 100 mg, or about 1 to about 50 mg per kilogram of body weightper day.

When a compound provided herein, is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound provided herein unit dose forms ofthe agent and the compound provided herein can be adjusted accordingly.

3. Kits

In some embodiments, provided herein are kits. The kits can include acompound or pharmaceutical composition as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits can also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the pharmaceutical composition, and/orwhich describe dosing, administration, side effects, drug interactions,or other information useful to the health care provider. Suchinformation can be based on the results of various studies, for example,studies using experimental animals involving in vivo models and studiesbased on human clinical trials.

In some embodiments, a memory aid is provided with the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

The kit can further contain another agent. In some embodiments, thecompound as disclosed herein and the agent are provided as separatepharmaceutical compositions in separate containers within the kit. Insome embodiments, the compound as disclosed herein and the agent areprovided as a single pharmaceutical composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and can be includedin the kit. In other embodiments, kits can further comprise devices thatare used to administer the active agents. Examples of such devicesinclude, but are not limited to, syringes, drip bags, patches, andinhalers. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits can also, in some embodiments,be marketed directly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. The strength of the sheet is such that the tablets or capsulescan be removed from the blister pack by manually applying pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Therapeutic Methods

Phosphoinositide 3-kinases (PI3Ks) are members of a conserved family oflipid kinases that regulate numerous cell functions, includingproliferation, differentiation, cell survival and metabolism. Severalclasses of PI3Ks exist in mammalian cells, including Class IA subgroup(e.g., PI3K-α, β, δ), which are generally activated by receptor tyrosinekinases (RTKs); Class IB (e.g., PI3K-γ), which is activated by G-proteincoupled receptors (GPCRs), among others. PI3Ks exert their biologicalactivities via a “PI3K-mediated signaling pathway” that includes severalcomponents that directly and/or indirectly transduce a signal triggeredby a PI3K, including the generation of second messengerphophotidylinositol, 3,4,5-triphosphate (PIP3) at the plasma membrane,activation of heterotrimeric G protein signaling, and generation offurther second messengers such as cAMP, DAG, and IP3, all of which leadsto an extensive cascade of protein kinase activation (reviewed inVanhaesebroeck, B. et al. (2001) Annu Rev Biochem. 70:535-602). Forexample, PI3K-δ is activated by cellular receptors through interactionbetween the PI3K regulatory subunit (p85) SH2 domains, or through directinteraction with RAS. PIP3 produced by PI3K activates effector pathwaysdownstream through interaction with plextrin homology (PH) domaincontaining enzymes (e.g., PDK-1 and AKT [PKB]). (Fung-Leung W P. (2011)Cell Signal. 23(4):603-8). Unlike PI3K-δ, PI3K-γ is not associated witha regulatory subunit of the p85 family, but rather with a regulatorysubunit in the p101 family. PI3K-γ is associated with GPCRs, and isresponsible for the very rapid induction of PIP3. PI3K-γ can be alsoactivated by RAS.

In some embodiments, provided herein are methods of modulating a PI3Kkinase activity (e.g., selectively modulating) by contacting the kinasewith an effective amount of a compound, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein. Modulation can beinhibition (e.g., reduction) or activation (e.g., enhancement) of kinaseactivity. In some embodiments, provided herein are methods of inhibitingkinase activity by contacting the kinase with an effective amount of acompound as provided herein in solution. In some embodiments, providedherein are methods of inhibiting the kinase activity by contacting acell, tissue, organ that express the kinase of interest with a compoundprovided herein. In some embodiments, provided herein are methods ofinhibiting kinase activity in a subject by administering into thesubject an effective amount of a compound as provided herein. In someembodiments, the kinase activity is inhibited (e.g., reduced) by morethan about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% when contacted witha compound provided herein as compared to the kinase activity withoutsuch contact. In some embodiments, provided herein are methods ofinhibiting PI3 kinase activity in a subject (including mammals such ashumans) by contacting said subject with an amount of a compound asprovided herein sufficient to inhibit or reduce the activity of the PI3kinase in said subject.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from a PI3 kinase includingdifferent isoforms such as PI3 kinase α, PI3 kinase β, PI3 kinase γ, PI3kinase δ; DNA-PK; mTor; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEKreceptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3);Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1;Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor(IR); and IGFR.

As used herein, a “PI3K-mediated disorder” refers to a disease orcondition involving aberrant PI3K-mediated signaling pathway. In oneembodiment, provided herein is a method of treating a PI3K mediateddisorder in a subject, the method comprising administering atherapeutically effective amount of a compound or a pharmaceuticalcomposition as provided herein. In some embodiments, provided herein isa method of treating a PI3K-δ or PI3K-γ mediated disorder in a subject,the method comprising administering a therapeutically effective amountof a compound or a pharmaceutical composition as provided herein. Insome embodiments, provided herein is a method for inhibiting at leastone of PI3K-δ and PI3K-γ, the method comprising contacting a cellexpressing PI3K in vitro or in vivo with an effective amount of thecompound or composition provided herein. PI3Ks have been associated witha wide range of conditions, including immunity, cancer and thrombosis(reviewed in Vanhaesebroeck, B. et al. (2010) Current Topics inMicrobiology and Immunology, DOI 10.1007/82201065). For example, Class 1PI3Ks, particularly PI3K-γ and PI3K-δ isoforms, are highly expressed inleukocytes and have been associated with adaptive and innate immunity;thus, these PI3Ks are believed to be important mediators in inflammatorydisorders and hematologic malignancies (reviewed in Harris, S J et al.(2009) Curr Opin Investig Drugs 10(11):1151-62); Rommel C. et al. (2007)Nat Rev Immunol 7(3):191-201; Durand C A et al. (2009) J Immunol.183(9):5673-84; Dil N. Marshall A J. (2009) Mol Immunol. 46(10):1970-8;Al-Alwan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86).

Numerous publications support roles of PI3K-δ, PI3K-γ, and PI3K-β in thedifferentiation, maintenance, and activation of immune and malignantcells, as described in more detail below.

The importance of PI3K-δ in the development and function of B-cells issupported from inhibitor studies and genetic models. PI3K-δ is animportant mediator of B-cell receptor (BCR) signaling, and is upstreamof AKT, calcium flux, PLCγ, MAP kinase, P70S6k, and FOXO3a activation.PI3K-δ is also important in IL4R, S1P, and CXCR5 signaling, and has beenshown to modulate responses to toll-like receptors 4 and 9. Inhibitorsof PI3K-δ have shown the importance of PI3K-δ in B-cell development(Marginal zone and B1 cells), B-cell activation, chemotaxis, migrationand homing to lymphoid tissue, and in the control of immunoglobulinclass switching leading to the production of IgE. Clayton E et al.(2002) J Exp Med. 196(6):753-63; Bilancio A, et al. (2006) Blood107(2):642-50; Okkenhaug K. et al. (2002) Science 297(5583):1031-4;Al-Alvan M M et al. (2007) J Immunol. 178(4):2328-35; Zhang T T, et al.(2008) J Allergy Clin Immunol. 2008; 122(4):811-819.e2; Srinivasan L, etal. (2009) Cell 139(3):573-86)

In T-cells, PI3K-δ has been demonstrated to have a role in T-cellreceptor and cytokine signaling, and is upstream of AKT, PLCγ, andGSK3b. In PI3K-δ deletion or kinase-dead knock-in mice, or in inhibitorstudies, T-cell defects including proliferation, activation, anddifferentiation have been observed, leading to reduced T helper cell 2(TH2) response, memory T-cell specific defects (DTH reduction), defectsin antigen dependent cellular trafficking, and defects inchemotaxis/migration to chemokines (e.g., S1P, CCR7, CD62L). (Garçon F.et al. (2008) Blood 111(3):1464-71; Okkenhaug K et al. (2006). JImmunol. 177(8):5122-8; Soond D R, et al. (2010) Blood 115(11):2203-13;Reif K, (2004). J Immunol. 2004; 173(4):2236-40; Ji H. et al. (2007)Blood 110(8):2940-7; Webb L M, et al. (2005) J Immunol. 175(5):2783-7;Liu D, et al. (2010) J Immunol. 184(6):3098-105; Haylock-Jacobs S, etal. (2011) J Autoimmun. 2011; 36(3-4):278-87; Jarmin S J, et al. (2008)J Clin Invest. 118(3):1154-64).

In neutrophils, PI3K-δ along with PI3K-γ, and PI3K-β, contribute to theresponses to immune complexes, FCγRII signaling, including migration andneutrophil respiratory burst. Human neutrophils undergo rapid inductionof PIP3 in response to formyl peptide receptor (FMLP) or complementcomponent C5a (C5a) in a PI3K-γ dependent manner, followed by a longerPIP3 production period that is PI3K-δ dependent, and is essential forrespiratory burst. The response to immune complexes is contributed byPI3K-δ, PI3K-γ, and PI3K-β, and is an important mediator of tissuedamage in models of autoimmune disease (Randis T M et al. (2008) Eur JImmunol. 38(5):1215-24; Pinho V, (2007) J Immunol. 179(11):7891-8; SadhuC. et al. (2003) J Immunol. 170(5):2647-54; Condliffe A M et al. (2005)Blood 106(4):1432-40). It has been reported that in certain autoimmunediseases, perfrential activation of PI3Kβ may be involved. (Kulkarni etal., Immunology (2011) 4(168) ra23: 1-11). It was also reported thatPI3Kβ-deficient mice were highly protected in an FcγR-dependent model ofautoantibody-induced skin blistering and partially protected in anFcγR-dependent model of inflammatory arthritis, whereas combineddeficiency of PI3Kβ and PI3Kδ resulted in near complete protection ininflammatory arthritis. (Id.).

In macrophages collected from patients with chronic obstructivepulmonary disease (COPD), glucocorticoid responsiveness can be restoredby treatment of the cells with inhibitors of PI3K-δ. Macrophages alsorely on PI3K-δ and PI3K-γ for responses to immune complexes through thearthus reaction (FCgR and C5a signaling) (Randis T M, et al. (2008) EurJ Immunol. 38(5):1215-24; Marwick J A et al. (2009) Am J Respir CritCare Med. 179(7):542-8; Konrad S, et al. (2008) J Biol Chem.283(48):33296-303).

In mast cells, stem cell factor- (SCF) and IL3-dependent proliferation,differentiation and function are PI3K-δ dependent, as is chemotaxis. Theallergen/IgE crosslinking of FCgR1 resulting in cytokine release anddegranulation of the mast cells is severely inhibited by treatment withPI3K-δ inhibitors, suggesting a role for PI3K-δ in allergic disease (AliK et al. (2004) Nature 431(7011):1007-11; Lee K S, et al. (2006) FASEBJ. 20(3):455-65; Kim M S, et al. (2008) Trends Immunol. 29(10):493-501).

Natural killer (NK) cells are dependent on both PI3K-δ and PI3K-γ forefficient migration towards chemokines including CXCL10, CCL3, S1P andCXCL12, or in response to LPS in the peritoneum (Guo H, et al. (2008) JExp Med. 205(10):2419-35; Tassi I, et al. (2007) Immunity 27(2):214-27;Saudemont A, (2009) Proc Natl Acad Sci USA. 106(14):5795-800; Kim N, etal. (2007) Blood 110(9):3202-8).

The roles of PI3K-δ, PI3K-γ, and PI3K-β in the differentiation,maintenance, and activation of immune cells support a role for theseenzymes in inflammatory disorders ranging from autoimmune diseases(e.g., rheumatoid arthritis, multiple sclerosis) to allergicinflammatory disorders, such as asthma, and inflammatory respiratorydisease such as COPD. Extensive evidence is available in experimentalanimal models, or can be evaluated using art-recognized animal models.In an embodiment, described herein is a method of treating inflammatorydisorders ranging from autoimmune diseases (e.g., rheumatoid arthritis,multiple sclerosis) to allergic inflammatory disorders, such as asthmaand COPD using a compound described herein.

For example, inhibitors of PI3K-δ and/or -γ have been shown to haveanti-inflammatory activity in several autoimmune animal models forrheumatoid arthritis (Williams, O. et al. (2010) Chem Biol,17(2):123-34; WO 2009/088986; WO2009/088880; WO 2011/008302). PI3K-δ isexpressed in the RA synovial tissue (especially in the synovial liningwhich contains fibroblast-like synoviocytes (FLS), and selective PI3K-δinhibitors have been shown to be effective in inhibiting synoviocytegrowth and survival (Bartok et al. (2010) Arthritis Rheum 62 Suppl10:362). Several PI3K-δ and -γ inhibitors have been shown to amelioratearthritic symptoms (e.g., swelling of joints, reduction of serum-inducedcollagen levels, reduction of joint pathology and/or inflammation), inart-recognized models for RA, such as collagen-induced arthritis andadjuvant induced arthritis (WO 2009/088986; WO2009/088880; WO2011/008302).

The role of PI3K-δ has also been shown in models of T-cell dependentresponse, including the DTH model. In the murine experimental autoimmuneencephalomyelitis (EAE) model of multiple sclerosis, the PI3-γ/δ-doublemutant mice are resistant. PI3K-δ inhibitors have also been shown toblock EAE disease induction and development of TH-17 cells both in vitroand in vivo (Haylock-Jacobs, S. et al. (2011) J. Autoimmunity36(3-4):278-87).

Systemic lupus erythematosus (SLE) is a complex disease that atdifferent stages requires memory T-cells, B-cell polyclonal expansionand differentiation into plasma cells, and the innate immune response toendogenous damage associated molecular pattern molecules (DAMPS), andthe inflammatory responses to immune complexes through the complementsystem as well as the F_(C) receptors. The role of PI3K-δ and PI3K-γtogether in these pathways and cell types suggest that blockade with aninhibitor would be effective in these diseases. A role for PI3K in lupusis also predicted by two genetic models of lupus. The deletion ofphosphatase and tensin homolog (PTEN) leads to a lupus-like phenotype,as does a transgenic activation of Class 1 PI3Ks, which includes PI3K-δ.The deletion of PI3K-γ in the transgenically activated class 1A lupusmodel is protective, and treatment with a PI3K-γ selective inhibitor inthe murine MLR/lpr model of lupus improves symptoms (Barber, D F et al.(2006) J. Immunol. 176(1): 589-93).

In allergic disease, PI3K-δ has been shown by genetic models and byinhibitor treatment to be essential for mast-cell activation in apassive cutaneous anaphalaxis assay (Ali K et al. (2008) J Immunol.180(4):2538-44; Ali K, (2004) Nature 431(7011):1007-11). In a pulmonarymeasure of response to immune complexes (Arthus reaction) a PI3K-δknockout is resistant, showing a defect in macrophage activation and C5aproduction. Knockout studies and studies with inhibitors for both PI3K-δand PI3K-γ support a role for both of these enzymes in the ovalbumininduced allergic airway inflammation and hyper-responsiveness model (LeeK S et al. (2006) FASEB J. 20(3):455-65). Reductions of infiltration ofeosinophils, neutrophils, and lymphocytes as well as TH2 cytokines (IL4,IL5, and IL13) were seen with both PI3K-δ specific and dual PI3K-δ andPI3K-γ inhibitors in the Ova induced asthma model (Lee K S et al. (2006)J Allergy Clin Immunol 118(2):403-9).

PI3K-δ and PI3K-γ inhibition can be used in treating COPD. In the smokedmouse model of COPD, the PI3K-δ knockout does not develop smoke inducedglucocorticoid resistance, while wild-type and PI3K-γ knockout mice do.An inhaled formulation of dual PI3K-γ and PI3K-γ inhibitor blockedinflammation in a LPS or smoke COPD models as measured by neutrophiliaand glucocorticoid resistance (Doukas J, et al. (2009) J Pharmacol ExpTher. 328(3):758-65).

Class I PI3Ks, particularly PI3K-δ and PI3K-γ isoforms, are alsoassociated with cancers (reviewed, e.g., in Vogt, P K et al. (2010) CurrTop Microbiol Immunol. 347:79-104; Fresno Vara, J A et al. (2004) CancerTreat Rev. 30(2):193-204; Zhao, L and Vogt, P K. (2008) Oncogene27(41):5486-96). Inhibitors of PI3K, e.g., PI3K-δ and/or -γ, have beenshown to have anti-cancer activity (e.g., Courtney, K D et al. (2010) JClin Oncol. 28(6):1075-1083); Markman, B et al. (2010) Ann Oncol.21(4):683-91; Kong, D and Yamori, T (2009) Curr Med Chem.16(22):2839-54; Jimeno, A et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3542); Flinn, I W et al. (2009) J Clin Oncol. 27:156s (suppl;abstr 3543); Shapiro, G et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3500); Wagner, A J et al. (2009) J Clin Oncol. 27:146s (suppl;abstr 3501); Vogt, P K et al. (2006) Virology 344(1):131-8; Ward, S etal. (2003) Chem Biol. 10(3):207-13; WO 2011/041399; US 2010/0029693; US2010/0305096; US 2010/0305084). In an embodiment, described herein is amethod of treating cancer.

Types of cancer that can be treated with an inhibitor of PI3K(particularly, PI3K-δ and/or -γ) include, e.g., leukemia, chroniclymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia(e.g., Salmena, L et al. (2008) Cell 133:403-414; Chapuis, N et al.(2010) Clin Cancer Res. 16(22):5424-35; Khwaja, A (2010) Curr TopMicrobiol Immunol. 347:169-88); lymphoma, e.g., non-Hodgkin's lymphoma(e.g., Salmena, L et al. (2008) Cell 133:403-414); lung cancer, e.g.,non-small cell lung cancer, small cell lung cancer (e.g., Herrera, V Aet al. (2011) Anticancer Res. 31(3):849-54); melanoma (e.g., Haluska, Fet al. (2007) Semin Oncol. 34(6):546-54); prostate cancer (e.g., Sarker,D et al. (2009) Clin Cancer Res. 15(15):4799-805); glioblastoma (e.g.,Chen, J S et al. (2008) Mol Cancer Ther. 7:841-850); endometrial cancer(e.g., Bansal, N et al. (2009) Cancer Control. 16(1):8-13); pancreaticcancer (e.g., Furukawa, T (2008) J Gastroenterol. 43(12):905-11); renalcell carcinoma (e.g., Porta, C and Figlin, R A (2009) J Urol.182(6):2569-77); colorectal cancer (e.g., Saif, M W and Chu, E (2010)Cancer J. 16(3):196-201); breast cancer (e.g., Torbett, N E et al.(2008) Biochem J. 415:97-100); thyroid cancer (e.g., Brzezianska, E andPastuszak-Lewandoska, D (2011) Front Biosci. 16:422-39); and ovariancancer (e.g., Mazzoletti, M and Broggini, M (2010) Curr Med Chem.17(36):4433-47).

Numerous publications support a role of PI3K-δ and PI3K-γ in treatinghematological cancers. PI3K-δ and PI3K-γ are highly expressed in theheme compartment, and some solid tumors, including prostate, breast andglioblastomas (Chen J. S. et al. (2008) Mol Cancer Ther. 7(4):841-50;Ikeda H. et al. (2010) Blood 116(9):1460-8).

In hematological cancers including acute myeloid leukemia (AML),multiple myeloma (MM), and chronic lymphocytic leukemia (CLL),overexpression and constitutive activation of PI3K-δ supports the modelthat PI3K-δ inhibition would be therapeutic Billottet C, et al. (2006)Oncogene 25(50):6648-59; Billottet C, et al. (2009) Cancer Res.69(3):1027-36; Meadows, S A, 52^(nd) ASH Meeting and Exposition; 2010Dec. 4-7; Orlando, Fla.; Ikeda H, et al. (2010) Blood 116(9):1460-8;Herman S E et al. (2010) Blood 116(12):2078-88; Herman S E et al.(2011). Blood 117(16):4323-7. In an embodiment, described herein is amethod of treating hematological cancers including, but not limited toacute myeloid leukemia (AML), multiple myeloma (MM), and chroniclymphocytic leukemia (CLL).

A PI3K-δ inhibitor (CAL-101) has been evaluated in a phase 1 trial inpatients with haematological malignancies, and showed activity in CLL inpatients with poor prognostic characteristics. In CLL, inhibition ofPI3K-δ not only affects tumor cells directly, but it also affects theability of the tumor cells to interact with their microenvironment. Thismicroenvironment includes contact with and factors from stromal cells,T-cells, nurse like cells, as well as other tumor cells. CAL-101suppresses the expression of stromal and T-cell derived factorsincluding CCL3, CCL4, and CXCL13, as well as the CLL tumor cells'ability to respond to these factors. CAL-101 treatment in CLL patientsinduces rapid lymph node reduction and redistribution of lymphocytesinto the circulation, and affects tonic survival signals through theBCR, leading to reduced cell viability, and an increase in apoptosis.Single agent CAL-101 treatment was also active in mantle cell lymphomaand refractory non Hodgkin's lymphoma (Furman, R R, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.;Hoellenriegel, J, et al. 52^(nd) Annual ASH Meeting and Exposition; 2010Dec. 4-7; Orlando, Fla.; Webb, H K, et al. 52″ Annual ASH Meeting andExposition; 2010 Dec. 4-7; Orlando, Fla.; Meadows, et al. 52^(nd) AnnualASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Kahl, B, etal. 52^(nd) Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando,Fla.; Lannutti B J, et al. (2011) Blood 117(2):591-4).

PI3K-δ inhibitors have shown activity against PI3K-δ positive gliomas invitro (Kashishian A, et al. Poster presented at: The AmericanAssociation of Cancer Research 102^(nd) Annual Meeting; 2011 Apr. 2-6;Orlando, Fla.). PI3K-δ is the PI3K isoform that is most commonlyactivated in tumors where the PTEN tumor suppressor is mutated (Ward S,et al. (2003) Chem Biol. 10(3):207-13). In this subset of tumors,treatment with the PI3K-δ inhibitor either alone or in combination witha cytotoxic agent can be effective.

Another mechanism for PI3K-δ inhibitors to have an affect in solidtumors involves the tumor cells' interaction with theirmicro-environment. PI3K-δ, PI3K-γ, and PI3K-β are expressed in theimmune cells that infiltrate tumors, including tumor infiltratinglymphocytes, macrophages, and neutrophils. PI3K-δ inhibitors can modifythe function of these tumor-associated immune cells and how they respondto signals from the stroma, the tumor, and each other, and in this wayaffect tumor cells and metastasis (Hoellenriegel, J, et al. 52^(nd)Annual ASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.).

PI3K-δ is also expressed in endothelial cells. It has been shown thattumors in mice treated with PI3K-δ selective inhibitors are killed morereadily by radiation therapy. In this same study, capillary networkformation is impaired by the PI3K inhibitor, and it is postulated thatthis defect contributes to the greater killing with radiation. PI3K-δinhibitors can affect the way in which tumors interact with theirmicroenvironment, including stromal cells, immune cells, and endothelialcells and be therapeutic either on its own or in conjunction withanother therapy (Meadows, S A, et al. Paper presented at: 52^(nd) AnnualASH Meeting and Exposition; 2010 Dec. 4-7; Orlando, Fla.; Geng L, et al.(2004) Cancer Res. 64(14):4893-9).

In other embodiments, inhibition of PI3K (such as PI3K-δ and/or -γ) canbe used to treat a neuropsychiatric disorder, e.g., an autoimmune braindisorder. Infectious and immune factors have been implicated in thepathogenesis of several neuropsychiatric disorders, including, but notlimited to, Sydenham's chorea (SC) (Garvey, M. A. et al. (2005) J. ChildNeurol. 20:424-429), Tourette's syndrome (TS), obsessive compulsivedisorder (OCD) (Asbahr, F. R. et al. (1998) Am. J. Psychiatry155:1122-1124), attention deficit/hyperactivity disorder (AD/HD)(Hirschtritt, M. E. et al. (2008) Child Neuropsychol. 1:1-16; Peterson,B. S. et al. (2000) Arch. Gen. Psychiatry 57:364-372), anorexia nervosa(Sokol, M. S. (2000) J. Child Adolesc. Psychopharmacol. 10:133-145;Sokol, M. S. et al. (2002) Am. J. Psychiatry 159:1430-1432), depression(Leslie, D. L. et al. (2008) J. Am. Acad. Child Adolesc. Psychiatry47:1166-1172), and autism spectrum disorders (ASD) (Hollander, E. et al.(1999) Am. J. Psychiatry 156:317-320; Margutti, P. et al. (2006) Curr.Neurovasc. Res. 3:149-157). A subset of childhood obsessive compulsivedisorders and tic disorders has been grouped as Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococci (PANDAS). PANDASdisorders provide an example of disorders where the onset andexacerbation of neuropsychiatric symptoms is preceded by a streptococcalinfection (Kurlan, R., Kaplan, E. L. (2004) Pediatrics 113:883-886;Garvey, M. A. et al. (1998) J. Clin. Neurol. 13:413-423). Many of thePANDAS disorders share a common mechanism of action resulting fromantibody responses against streptococcal associated epitopes, such asGlcNAc, which produces neurological effects (Kirvan, C. A. et al. (2006)J. Neuroimmunol. 179:173-179). Autoantibodies recognizing centralnervous system (CNS) epitopes are also found in sera of most PANDASsubjects (Yaddanapudi, K. et al. (2010) Mol. Psychiatry 15:712-726).Thus, several neuropsychiatric disorders have been associated withimmune and autoimmune components, making them suitable for therapiesthat include PI3K-δ and/or -γ inhibition.

In certain embodiments, a method of treating (e.g., reducing orameliorating one or more symptoms of) a neuropsychiatric disorder,(e.g., an autoimmune brain disorder), using a PI3K-δ and/or -γ inhibitoris described, alone or in combination therapy. For example, one or morePI3K-δ and/or -γ inhibitors described herein can be used alone or incombination with any suitable therapeutic agent and/or modalities, e.g.,dietary supplement, for treatment of neuropsychiatric disorders.Exemplary neuropsychiatric disorders that can be treated with the PI3K-δand/or -γ inhibitors described herein include, but are not limited to,PANDAS disorders, Sydenham's chorea, Tourette's syndrome, obsessivecompulsive disorder, attention deficit/hyperactivity disorder, anorexianervosa, depression, and autism spectrum disorders. PervasiveDevelopmental Disorder (PDD) is an exemplary class of autism spectrumdisorders that includes Autistic Disorder, Asperger's Disorder,Childhood Disintegrative Disorder (CDD), Rett's Disorder and PDD-NotOtherwise Specified (PDD-NOS). Animal models for evaluating the activityof the PI3K-δ and/or -γ inhibitor are known in the art. For example, amouse model of PANDAS disorders is described in, e.g., Yaddanapudi, K.et al. (2010) supra; and Hoffman, K. I. et al. (2004) J. Neurosci.24:1780-1791.

In some embodiments, provided herein are methods of using the compounds,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided hereinto treat disease conditions, including, but not limited to, diseasesassociated with malfunctioning of one or more types of PI3 kinase. Adetailed description of conditions and disorders mediated by p110δkinase activity is set forth in Sadu et al., WO 01/81346, which isincorporated herein by reference in its entirety for all purposes.

In some embodiments, the disclosure relates to a method of treating ahyperproliferative disorder in a subject that comprises administering tosaid subject a therapeutically effective amount of a compound, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein.In some embodiments, said method relates to the treatment of cancer suchas acute myeloid leukemia, thymus, brain, lung, squamous cell, skin,eye, retinoblastoma, intraocular melanoma, oral cavity andoropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast,cervical, head, neck, renal, kidney, liver, ovarian, prostate,colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS,AIDS-related (e.g., Lymphoma and Kaposi's Sarcoma) or viral-inducedcancer. In some embodiments, said method relates to the treatment of anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e.g., psoriasis), restenosis, or prostate (e.g., benignprostatic hypertrophy (BPH)).

Patients that can be treated with compounds, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, according tothe methods as provided herein include, for example, but not limited to,patients that have been diagnosed as having psoriasis; restenosis;atherosclerosis; BPH; breast cancer such as a ductal carcinoma in ducttissue in a mammary gland, medullary carcinomas, colloid carcinomas,tubular carcinomas, and inflammatory breast cancer; ovarian cancer,including epithelial ovarian tumors such as adenocarcinoma in the ovaryand an adenocarcinoma that has migrated from the ovary into theabdominal cavity; uterine cancer; cervical cancer such as adenocarcinomain the cervix epithelial including squamous cell carcinoma andadenocarcinomas; prostate cancer, such as a prostate cancer selectedfrom the following: an adenocarcinoma or an adenocarinoma that hasmigrated to the bone; pancreatic cancer such as epitheliod carcinoma inthe pancreatic duct tissue and an adenocarcinoma in a pancreatic duct;bladder cancer such as a transitional cell carcinoma in urinary bladder,urothelial carcinomas (transitional cell carcinomas), tumors in theurothelial cells that line the bladder, squamous cell carcinomas,adenocarcinomas, and small cell cancers; leukemia such as acute myeloidleukemia (AML), acute lymphocytic leukemia, chronic lymphocyticleukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, NK cell leukemia (e.g., blasticplasmacytoid dendritic cell neoplasm), acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocyticleukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome(MDS); bone cancer; lung cancer such as non-small cell lung cancer(NSCLC), which is divided into squamous cell carcinomas,adenocarcinomas, and large cell undifferentiated carcinomas, and smallcell lung cancer; skin cancer such as basal cell carcinoma, melanoma,squamous cell carcinoma and actinic keratosis, which is a skin conditionthat sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; lymphoma suchas diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, NK celllymphoma (e.g., blastic plasmacytoid dendritic cell neoplasm), and smallnon-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancersincluding hepatitis B virus (HBV), hepatitis C virus (HCV), andhepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) andadult T-cell leukemia/lymphoma; and human papilloma virus (HPV) andcervical cancer; central nervous system cancers (CNS) such as primarybrain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMüllerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer.

In one embodiment, provided herein is a method of treating aninflammation disorder, including autoimmune diseases in a subject. Themethod comprises administering to said subject a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein. Examples of autoimmunediseases includes but is not limited to acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), aplastic anemia, autoimmune hepatitis, autoimmune skindisease, coeliac disease, Crohn's disease, Diabetes mellitus (type 1),Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS),Hashimoto's disease, lupus erythematosus, multiple sclerosis, myastheniagravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord'sthyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis,psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis (also known as “giant cell arteritis”),warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis (e.g., inflammatory alopecia), Chagas disease, chronicfatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, and vulvodynia. Other disorders includebone-resorption disorders and thrombosis.

Inflammation takes on many forms and includes, but is not limited to,acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse,disseminated, exudative, fibrinous, fibrosing, focal, granulomatous,hyperplastic, hypertrophic, interstitial, metastatic, necrotic,obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple,specific, subacute, suppurative, toxic, traumatic, and/or ulcerativeinflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoidarthritis and Reiter's arthritis), ankylosing spondylitis, amylosis,amyotrophic lateral sclerosis, autoimmune diseases, allergies orallergic reactions, atherosclerosis, bronchitis, bursitis, chronicprostatitis, conjunctivitis, Chagas disease, chronic obstructivepulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., typeI diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g.,psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, polymyalgiarheumatic, reperfusion injury, regional enteritis, rheumatic fever,systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia.

Immune disorders, such as auto-immune disorders, include, but are notlimited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), relapsing polychondritis (e.g.,atrophic polychondritis and systemic polychondromalacia), and disordersameliorated by a gastroprokinetic agent (e.g., ileus, postoperativeileus and ileus during sepsis; gastroesophageal reflux disease (GORD, orits synonym GERD); eosinophilic esophagitis, gastroparesis such asdiabetic gastroparesis; food intolerances and food allergies and otherfunctional bowel disorders, such as non-ulcerative dyspepsia (NUD) andnon-cardiac chest pain (NCCP, including costo-chondritis)). In certainembodiments, a method of treating inflammatory or autoimmune diseases isprovided comprising administering to a subject (e.g., a mammal) atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, thatselectively inhibit PI3K-δ and/or PI3K-γ as compared to all other type IPI3 kinases.

Such selective inhibition of PI3K-δ and/or PI3K-γ can be advantageousfor treating any of the diseases or conditions described herein. Forexample, selective inhibition of PI3K-δ can inhibit inflammatoryresponses associated with inflammatory diseases, autoimmune disease, ordiseases related to an undesirable immune response including, but notlimited to asthma, emphysema, allergy, dermatitis, rheumatoid arthritis,psoriasis, lupus erythematosus, anaphylaxsis, or graft versus hostdisease. Selective inhibition of PI3K-δ can further provide for areduction in the inflammatory or undesirable immune response without aconcomittant reduction in the ability to reduce a bacterial, viral,and/or fungal infection. Selective inhibition of both PI3K-δ and PI3K-γcan be advantageous for inhibiting the inflammatory response in thesubject to a greater degree than that would be provided for byinhibitors that selectively inhibit PI3K -δ or PI3K-γ alone. In oneaspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rheumatoid arthritis including,but not limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In some embodiments, provided herein are methods for treating disordersor conditions in which the δ isoform of PI3K is implicated to a greaterextent than other PI3K isoforms such as PI3K-α and/or -β. Selectiveinhibition of PI3K-δ and/or PI3K-γ can provide advantages over usingless selective compounds which inhibit PI3K-α and/or -β, such as animproved side effects profile or lessened reduction in the ability toreduce a bacterial, viral, and/or fungal infection.

In other embodiments, provided herein are methods of using a compound,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,to treat respiratory diseases including, but not limited to diseasesaffecting the lobes of lung, pleural cavity, bronchial tubes, trachea,upper respiratory tract, or the nerves and muscle for breathing. Forexample, methods are provided to treat obstructive pulmonary disease.Chronic obstructive pulmonary disease (COPD) is an umbrella term for agroup of respiratory tract diseases that are characterized by airflowobstruction or limitation. Conditions included in this umbrella terminclude, but are not limited to: chronic bronchitis, emphysema, andbronchiectasis.

In another embodiment, the compounds, or a pharmaceutically acceptableform (e.g., pharmaceutically acceptable salts, hydrates, solvates,isomers, prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein can be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

In some embodiments, the disclosure provides a method of treatingdiseases related to vasculogenesis or angiogenesis in a subject thatcomprises administering to said subject a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein. In some embodiments,said method is for treating a disease selected from tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis and chronicinflammatory demyelinating polyneuropathy, atherosclerosis, inflammatorybowel disease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In addition, the compounds described herein can be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

In some embodiments, provided herein is a method of treating acardiovascular disease in a subject that comprises administering to saidsubject a therapeutically effective amount of a compound as providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof. Examples of cardiovascularconditions include, but are not limited to atherosclerosis, restenosis,vascular occlusion and carotid obstructive disease.

In some embodiments, the disclosure relates to a method of treatingdiabetes in a subject that comprises administering to said subject atherapeutically effective amount of a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein.

In addition, the compounds, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used to treatacne. In certain embodiments, the inflammatory condition and/or immunedisorder is a skin condition. In some embodiments, the skin condition ispruritus (itch), psoriasis, eczema, burns or dermatitis. In certainembodiments, the skin condition is psoriasis. In certain embodiments,the skin condition is pruritis.

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

Further, the compounds, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used for thetreatment of glomerulonephritis. Glomerulonephritis is a primary orsecondary autoimmune renal disease characterized by inflammation of theglomeruli. It can be asymptomatic, or present with hematuria and/orproteinuria. There are many recognized types, divided in acute, subacuteor chronic glomerulonephritis. Causes are infectious (bacterial, viralor parasitic pathogens), autoimmune or paraneoplastic.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of multiorgan failure. Also provided herein arecompounds, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or pharmaceuticalcompositions as provided herein, for the treatment of liver diseases(including diabetes), gall bladder disease (including gallstones),pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or pain in asubject.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the prevention of blastocyte implantation in a subject.

In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of disorders involving platelet aggregation orplatelet adhesion, including, but not limited to Idiopathicthrombocytopenic purpura, Bernard-Soulier syndrome, Glanzmann'sthrombasthenia, Scott's syndrome, von Willebrand disease,Hermansky-Pudlak Syndrome, and Gray platelet syndrome.

In some embodiments, compounds, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, are provided fortreating a disease which is skeletal muscle atrophy, skeletal or musclehypertrophy. In some embodiments, provided herein are compounds, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,for the treatment of disorders that include, but are not limited to,cancers as discussed herein, transplantation-related disorders (e.g.,lowering rejection rates, graft-versus-host disease, etc.), muscularsclerosis (MS), allergic disorders (e.g., arthritis, allergicencephalomyelitis) and other immunosuppressive-related disorders,metabolic disorders (e.g., diabetes), reducing intimal thickeningfollowing vascular injury, and misfolded protein disorders (e.g.,Alzheimer's Disease, Gaucher's Disease, Parkinson's Disease,Huntington's Disease, cystic fibrosis, macular degeneration, retinitispigmentosa, and prion disorders) (as mTOR inhibition can alleviate theeffects of misfolded protein aggregates). The disorders also includehamartoma syndromes, such as tuberous sclerosis and Cowden Disease (alsotermed Cowden syndrome and multiple hamartoma syndrome).

Additionally, the compounds, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), Addison's disease, antiphospholipid antibody syndrome (APS),amyloidosis (including systemic and localized amyloidosis; and primaryand secondary amyloidosis), aplastic anemia, autoimmune hepatitis,coeliac disease, crohn's disease, diabetes mellitus (type I),eosinophilic gastroenterides, goodpasture's syndrome, graves' disease,guillain-barré syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus (including cutaneous lupus erythematosusand systemic lupus erythematosus), myasthenia gravis, opsoclonusmyoclonus syndrome (OMS), optic neuritis, ord's thyroiditis,ostheoarthritis, uveoretinitis, pemphigus, polyarthritis, primarybiliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporalarteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis,alopecia universalis, chagas' disease, chronic fatigue syndrome,dysautonomia, endometriosis, hidradenitis suppurativa, interstitialcystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis,vitiligo, vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis (e.g., ocular uveitis), vaginitis,vasculitis, or vulvitis.

In another aspect, provided herein are methods of disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Themethod includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound as provided herein.

In another aspect, methods are provided for treating ophthalmic diseaseby administering one or more of the subject compounds or pharmaceuticalcompositions to the eye of a subject.

In certain embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: Crohn's disease; cutaneous lupus;multiple sclerosis; rheumatoid arthritis; and systemic lupuserythematosus.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: ankylosing spondylitis; chronicobstructive pulmonary disease; myasthenia gravis; ocular uveitis,psoriasis; and psoriatic arthritis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: adult-onset Still's disease;inflammatory alopecia; amyloidosis; antiphospholipid syndrome;autoimmune hepatitis; autoimmune skin disease, Behcet's disease; chronicinflammatory demyelinating polyneuropathy; eosinophilic gastroenteritis;inflammatory myopathies, pemphigus, polymyalgia rheumatica; relapsingpolychondritis; Sjorgen's syndrome; temporal arthritis; ulcerativecolitis; vasculis; vitiligo, and Wegner's granulomatosis.

In other embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: gout flare; sacoidosis; and systemicsclerosis.

In certain embodiments, provided herein are methods of treating,preventing and/or managing a disease or a disorder using a compound, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,wherein the disease or disorder is: asthma; arthritis (e.g., rheumatoidarthritis and psoriatic arthritis); psoriasis; scleroderma; myositis(e.g., dermatomyositis); lupus (e.g., cutaneous lupus erythematosus(“CLE”) or systemic lupus erythematosus (“SLE”)); or Sjögren's syndrome.

Efficacy of a compound provided herein in treating, preventing and/ormanaging the disease or disorder can be tested using various animalmodels known in the art. For example: efficacy in treating, preventingand/or managing asthma can be assessed using ova induced asthma modeldescribed, for example, in Lee et al. (2006) J Allergy Clin Immunol118(2):403-9; efficacy in treating, preventing and/or managing arthritis(e.g., rheumatoid or psoriatic arthritis) can be assessed usingautoimmune animal models described, for example, in Williams et al.(2010) Chem Biol, 17(2):123-34, WO 2009/088986, WO2009/088880, and WO2011/008302; efficacy in treating, preventing and/or managing psoriasiscan be assessed using transgenic or knockout mouse model with targetedmutations in epidermis, vasculature or immune cells, mouse modelresulting from spontaneous mutations, and immunodeficient mouse modelwith xenotransplantation of human skin or immune cells, all of which aredescribed, for example, in Boehncke et al. (2007) Clinics inDermatology, 25: 596-605; efficacy in treating, preventing and/ormanaging fibrosis or fibrotic condition can be assessed using theunilateral ureteral obstruction model of renal fibrosis (see Chevalieret al., Kidney International (2009) 75:1145-1152), the bleomycin inducedmodel of pulmonary fibrosis (see Moore and Hogaboam, Am. J. Physiol.Lung. Cell. Mol. Physiol. (2008) 294:L152-L160), a variety ofliver/biliary fibrosis models (see Chuang et al., Clin Liver Dis (2008)12:333-347 and Omenetti, A. et al. (2007) Laboratory Investigation87:499-514 (biliary duct-ligated model)), or a number of myelofibrosismouse models (see Varicchio, L. et al. (2009) Expert Rev. Hematol.2(3):315-334); efficacy in treating, preventing and/or managingscleroderma can be assessed using mouse model induced by repeated localinjections of bleomycin (“BLM”) described, for example, in Yamamoto etal. (1999) J Invest Dermatol 112: 456-462; efficacy in treating,preventing and/or managing dermatomyositis can be assessed usingmyositis mouse model induced by immunization with rabbit myosindescribed, for example, in Phyanagi et al. (2009) Arthritis &Rheumatism, 60(10): 3118-3127; efficacy in treating, preventing and/ormanaging lupus (e.g., CLE or SLE) can be assessed using various animalmodels described, for example, in Ghoreishi et al. (2009) Lupus, 19:1029-1035, Ohl et al. (2011) Journal of Biomedicine and Biotechnology,Article ID 432595 (14 pages), Xia et al. (2011) Rheumatology,50:2187-2196, Pau et al. (2012) PLoS ONE, 7(5):e36761 (15 pages),Mustafa et al. (2011) Toxicology, 290:156-168, Ichikawa et al. (2012)Arthritis and Rheumatism, 62(2): 493-503, Ouyang et al. (2012) J MolMed, DOI 10.1007/s00109-012-0866-3 (10 pages), Rankin et al. (2012)Journal of Immunology, 188:1656-1667; and efficacy in treating,preventing and/or managing Sjögren's syndrome can be assessed usingvarious mouse models described, for example, in Chiorini et al. (2009)Journal of Autoimmunity, 33: 190-196.

In one embodiment, provided herein is a method of treating, preventingand/or managing asthma. As used herein, “asthma” encompasses airwayconstriction regardless of the cause. Common triggers of asthma include,but are not limited to, exposure to an environmental stimulants (e.g.,allergens), cold air, warm air, perfume, moist air, exercise orexertion, and emotional stress. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith asthma. Examples of the symptoms include, but are not limited to,severe coughing, airway constriction and mucus production.

In one embodiment, provided herein is a method of treating, preventingand/or managing arthritis. As used herein, “arthritis” encompasses alltypes and manifestations of arthritis. Examples include, but are notlimited to, crystalline arthritis, osteoarthritis, psoriatic arthritis,gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter'sarthritis. In one embodiment, the disease or disorder is rheumatoidarthritis. In another embodiment, the disease or disorder is psoriaticarthritis. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with arthritis. Examplesof the symptoms include, but are not limited to, joint pain, whichprogresses into joint deformation, or damages in body organs such as inblood vessels, heart, lungs, skin, and muscles.

In one embodiment, provided herein is a method of treating, preventingand/or managing psoriasis. As used herein, “psoriasis” encompasses alltypes and manifestations of psoriasis. Examples include, but are notlimited to, plaque psoriasis (e.g., chronic plaque psoriasis, moderateplaque psoriasis and severe plaque psoriasis), guttate psoriasis,inverse psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermicpsoriasis, psoriasis associated with inflammatory bowel disease (IBD),and psoriasis associated with rheumatoid arthritis (RA). Also providedherein is a method of treating, preventing and/or managing one or moresymptoms associated with psoriasis. Examples of the symptoms include,but are not limited to: red patches of skin covered with silvery scales;small scaling spots; dry, cracked skin that may bleed; itching; burning;soreness; thickened, pitted or ridged nails; and swollen and stiffjoints.

In one embodiment, provided herein is a method of treating, preventingand/or managing fibrosis and fibrotic condition. As used herein,“fibrosis” or “fibrotic condition encompasses all types andmanifestations of fibrosis or fibrotic condition. Examples include, butare not limited to, formation or deposition of tissue fibrosis; reducingthe size, cellularity (e.g., fibroblast or immune cell numbers),composition; or cellular content, of a fibrotic lesion; reducing thecollagen or hydroxyproline content, of a fibrotic lesion; reducingexpression or activity of a fibrogenic protein; reducing fibrosisassociated with an inflammatory response; decreasing weight lossassociated with fibrosis; or increasing survival.

In certain embodiments, the fibrotic condition is primary fibrosis. Inone embodiment, the fibrotic condition is idiopathic. In otherembodiments, the fibrotic condition is associated with (e.g., issecondary to) a disease (e.g., an infectious disease, an inflammatorydisease, an autoimmune disease, a malignant or cancerous disease, and/ora connective disease); a toxin; an insult (e.g., an environmental hazard(e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarettesmoking, a wound); a medical treatment (e.g., surgical incision,chemotherapy or radiation), or a combination thereof.

In some embodiments, the fibrotic condition is associated with anautoimmune disease selected from scleroderma or lupus, e.g., systemiclupus erythematosus. In some embodiments, the fibrotic condition issystemic. In some embodiments, the fibrotic condition is systemicsclerosis (e.g., limited systemic sclerosis, diffuse systemic sclerosis,or systemic sclerosis sine scleroderma), nephrogenic systemic fibrosis,cystic fibrosis, chronic graft vs. host disease, or atherosclerosis.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung, a fibrotic condition of the liver, a fibrotic condition ofthe heart or vasculature, a fibrotic condition of the kidney, a fibroticcondition of the skin, a fibrotic condition of the gastrointestinaltract, a fibrotic condition of the bone marrow or a hematopoietictissue, a fibrotic condition of the nervous system, a fibrotic conditionof the eye, or a combination thereof.

In other embodiment, the fibrotic condition affects a tissue chosen fromone or more of muscle, tendon, cartilage, skin (e.g., skin epidermis orendodermis), cardiac tissue, vascular tissue (e.g., artery, vein),pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterinetissue, ovarian tissue, neural tissue, testicular tissue, peritonealtissue, colon, small intestine, biliary tract, gut, bone marrow,hematopoietic tissue, or eye (e.g., retinal) tissue.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe eye. In some embodiments, the fibrotic condition is glaucoma,macular degeneration (e.g., age-related macular degeneration), macularedema (e.g., diabetic macular edema), retinopathy (e.g., diabeticretinopathy), or dry eye disease.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the lung. In certain embodiments, the fibrotic condition of the lungis chosen from one or more of: pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lungdisease, cryptogenic fibrosing alveolitis (CFA), bronchiectasis, andscleroderma lung disease. In one embodiment, the fibrosis of the lung issecondary to a disease, a toxin, an insult, a medical treatment, or acombination thereof. For example, the fibrosis of the lung can beassociated with (e.g., secondary to) one or more of: a disease processsuch as asbestosis and silicosis; an occupational hazard; anenvironmental pollutant; cigarette smoking; an autoimmune connectivetissue disorders (e.g., rheumatoid arthritis, scleroderma and systemiclupus erythematosus (SLE)); a connective tissue disorder such assarcoidosis; an infectious disease, e.g., infection, particularlychronic infection; a medical treatment, including but not limited to,radiation therapy, and drug therapy, e.g., chemotherapy (e.g., treatmentwith as bleomycin, methotrexate, amiodarone, busulfan, and/ornitrofurantoin). In one embodiment, the fibrotic condition of the lungtreated with the methods of the invention is associated with (e.g.,secondary to) a cancer treatment, e.g., treatment of a cancer (e.g.,squamous cell carcinoma, testicular cancer, Hodgkin's disease withbleomycin). In one embodiment, the fibrotic condition of the lung isassociated with an autoimmune connective tissue disorder (e.g.,scleroderma or lupus, e.g., SLE).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the liver. In certain embodiments, the fibrotic condition of theliver is chosen from one or more of: fatty liver disease, steatosis(e.g., nonalcoholic steatohepatitis (NASH), cholestatic liver disease(e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol inducedliver fibrosis, biliary duct injury, biliary fibrosis, orcholangiopathies. In other embodiments, hepatic or liver fibrosisincludes, but is not limited to, hepatic fibrosis associated withalcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B orD), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD),progressive massive fibrosis, exposure to toxins or irritants (e.g.,alcohol, pharmaceutical drugs and environmental toxins).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the heart. In certain embodiments, the fibrotic condition of theheart is myocardial fibrosis (e.g., myocardial fibrosis associated withradiation myocarditis, a surgical procedure complication (e.g.,myocardial post-operative fibrosis), infectious diseases (e.g., Chagasdisease, bacterial, trichinosis or fungal myocarditis)); granulomatous,metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis);developmental disorders (e.g, endocardial fibroelastosis);arteriosclerotic, or exposure to toxins or irritants (e.g., drug inducedcardiomyopathy, drug induced cardiotoxicity, alcoholic cardiomyopathy,cobalt poisoning or exposure). In certain embodiments, the myocardialfibrosis is associated with an inflammatory disorder of cardiac tissue(e.g., myocardial sarcoidosis). In some embodiments, the fibroticcondition is a fibrotic condition associated with a myocardialinfarction. In some embodiments, the fibrotic condition is a fibroticcondition associated with congestive heart failure.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the kidney. In certain embodiments, the fibrotic condition of thekidney is chosen from one or more of: renal fibrosis (e.g., chronickidney fibrosis), nephropathies associated with injury/fibrosis (e.g.,chronic nephropathies associated with diabetes (e.g., diabeticnephropathy)), lupus, scleroderma of the kidney, glomerular nephritis,focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosisassociated with human chronic kidney disease (CKD), chronic progressivenephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction,chronic uremia, chronic interstitial nephritis, radiation nephropathy,glomerulosclerosis, progressive glomerulonephrosis (PGN),endothelial/thrombotic microangiopathy injury, HIV-associatednephropathy, or fibrosis associated with exposure to a toxin, anirritant, or a chemotherapeutic agent. In one embodiment, the fibroticcondition of the kidney is scleroderma of the kidney. In someembodiments, the fibrotic condition of the kidney is transplantnephropathy, diabetic nephropathy, lupus nephritis, or focal segmentalglomerulosclerosis (FSGS).

In certain embodiments, the fibrotic condition is a fibrotic conditionof the skin. In certain embodiments, the fibrotic condition of the skinis chosen from one or more of: skin fibrosis (e.g., hypertrophicscarring, keloid), scleroderma, nephrogenic systemic fibrosis (e.g.,resulting after exposure to gadolinium (which is frequently used as acontrast substance for MRIs) in patients with severe kidney failure),and keloid.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the gastrointestinal tract. In certain embodiments, the fibroticcondition is chosen from one or more of: fibrosis associated withscleroderma; radiation induced gut fibrosis; fibrosis associated with aforegut inflammatory disorder such as Barrett's esophagus and chronicgastritis, and/or fibrosis associated with a hindgut inflammatorydisorder, such as inflammatory bowel disease (IBD), ulcerative colitisand Crohn's disease. In some embodiments, the fibrotic condition of thegastrointestinal tract is fibrosis associated with scleroderma.

In certain embodiments, the fibrotic condition is a fibrotic conditionof the bone marrow or a hematopoietic tissue. In certain embodiments,the fibrotic condition of the bone marrow is an intrinsic feature of achronic myeloproliferative neoplasm of the bone marrow, such as primarymyelofibrosis (also referred to herein as agnogenic myeloid metaplasiaor chronic idiopathic myelofibrosis). In other embodiments, the bonemarrow fibrosis is associated with (e.g., is secondary to) a malignantcondition or a condition caused by a clonal proliferative disease. Inother embodiments, the bone marrow fibrosis is associated with ahematologic disorder (e.g., a hematologic disorder chosen from one ormore of polycythemia vera, essential thrombocythemia, myelodysplasia,hairy cell leukemia, lymphoma (e.g., Hodgkin or non-Hodgkin lymphoma),multiple myeloma or chronic myelogeneous leukemia (CML)). In yet otherembodiments, the bone marrow fibrosis is associated with (e.g.,secondary to) a non-hematologic disorder (e.g., a non-hematologicdisorder chosen from solid tumor metastasis to bone marrow, anautoimmune disorder (e.g., systemic lupus erythematosus, scleroderma,mixed connective tissue disorder, or polymyositis), an infection (e.g.,tuberculosis), or secondary hyperparathyroidism associated with vitaminD deficiency. In some embodiments, the fibrotic condition is idiopathicor drug-induced myelofibrosis. In some embodiments, the fibroticcondition of the bone marrow or hematopoietic tissue is associated withsystemic lupus erythematosus or scleroderma.

In one embodiment, provided herein is a method of treating, preventingand/or managing scleroderma. Scleroderma is a group of diseases thatinvolve hardening and tightening of the skin and/or other connectivetissues. Scleroderma may be localized (e.g., affecting only the skin) orsystemic (e.g., affecting other systems such as, e.g., blood vesselsand/or internal organs). Common symptoms of scleroderma includeRaynaud's phenomenon, gastroesophageal reflux disease, and skin changes(e.g., swollen fingers and hands, or thickened patches of skin). In someembodiments, the scleroderma is localized, e.g., morphea or linearscleroderma. In some embodiments, the condition is a systemic sclerosis,e.g., limited systemic sclerosis, diffuse systemic sclerosis, orsystemic sclerosis sine scleroderma.

Localized scleroderma (localized cutaneous fibrosis) includes morpheaand linear scleroderma. Morphea is typically characterized byoval-shaped thickened patches of skin that are white in the middle, witha purple border. Linear scleroderma is more common in children. Symptomsof linear scleroderma may appear mostly on one side of the body. Inlinear scleroderma, bands or streaks of hardened skin may develop on oneor both arms or legs or on the forehead. En coup de sabre (frontallinear scleroderma or morphea en coup de sabre) is a type of localizedscleroderma typically characterized by linear lesions of the scalp orface.

Systemic scleroderma (systemic sclerosis) includes, e.g., limitedsystemic sclerosis (also known as limited cutaneous systemic sclerosis,or CREST syndrome), diffuse systemic sclerosis (also known as diffusecutaneous systemic sclerosis), and systemic sclerosis sine scleroderma.CREST stands for the following complications that may accompany limitedscleroderma: calcinosis (e.g., of the digits), Raynaud's phenomenon,esophageal dysfunction, sclerodactyl), and telangiectasias. Typically,limited scleroderma involves cutaneous manifestations that mainly affectthe hands, arms, and face. Limited and diffuse subtypes aredistinguished based on the extent of skin involvement, with sparing ofthe proximal limbs and trunk in limited disease. See, e.g., Denton, C.P. et al. (2006), Nature Clinical Practice Rheumatology, 2(3):134-143.The limited subtype also typically involves a long previous history ofRaynaud's phenomenon, whereas in the diffuse subtype, onset of Raynaud'sphenomenon can be simultaneous with other manifestations or might occurlater. Both limited and diffuse subtypes may involve internal organs.Typical visceral manifestations of limited systemic sclerosis includeisolated pulmonary hypertension, severe bowel involvement, and pulmonaryfibrosis. Typical visceral manifestations of diffuse systemic sclerosisinclude renal crisis, lung fibrosis, and cardiac disease. Diffusesystemic sclerosis typically progresses rapidly and affects a large areaof the skin and one or more internal organs (e.g., kidneys, esophagus,heart, or lungs). Systemic sclerosis sine scleroderma is a rare disorderin which patients develop vascular and fibrotic damage to internalorgans in the absence of cutaneous sclerosis.

In one embodiment, provided herein is a method of treating, preventingand/or managing inflammatory myopathies. As used herein, “inflammatorymyopathies” encompass all types and manifestations of inflammatorymyopathies. Examples include, but are not limited to, muscle weakness(e.g., proximal muscle weakness), skin rash, fatigue after walking orstanding, tripping or falling, dysphagia, dysphonia, difficultybreathing, muscle pain, tender muscles, weight loss, low-grade fever,inflamed lungs, light sensitivity, calcium deposits (calcinosis) underthe skin or in the muscle, as well as biological concomitants ofinflammatory myopathies as disclosed herein or as known in the art.Biological concomitants of inflammatory myopathies (e.g.,dermatomyositis) include, e.g., altered (e.g., increased) levels ofcytokines (e.g., Type I interferons (e.g., IFN-α and/or IFN-β),interleukins (e.g., IL-6, IL-10, IL-15, IL-17 and IL-18), and TNF-α),TGF-β, B-cell activating factor (BAFF), overexpression of IFN induciblegenes (e.g., Type 1 IFN inducible genes). Other biological concomitantsof inflammatory myopathies can include, e.g., an increased erythrocytesedimentation rate (ESR) and/or elevated level of creatine kinase.Further biological concomitants of inflammatory myopathies can includeautoantibodies, e.g., anti-synthetase autoantibodies (e.g., anti-Jolantibodies), anti-signal recognition particle antibodies (anti-SRP),anti-Mi-2 antibodies, anti-p155 antibodies, anti-PM/Sci antibodies, andanti-RNP antibodies.

The inflammatory myopathy can be an acute inflammatory myopathy or achronic inflammatory myopathy. In some embodiments, the inflammatorymyopathy is a chronic inflammatory myopathy dermatomyositis,polymyositis, or inclusion body myositis). In some embodiments, theinflammatory myopathy is caused by an allergic reaction, another disease(e.g., cancer or a connective tissue disease), exposure to a toxicsubstance, a medicine, or an infectious agent (e.g., a virus). In someembodiments, the inflammatory myopathy is associated with lupus,rheumatoid arthritis, or systemic sclerosis. In some embodiments, theinflammatory myopathy is idiopathic. In some embodiments, theinflammatory myopathy is selected from polymyositis, dermatomyositis,inclusion body myositis, and immune-mediated necrotizing myopathy. Insome embodiments, the inflammatory myopathy is dermatomyositis.

In another embodiment, provided herein is a method of treating,preventing and/or managing a skin condition (e.g., a dermatitis). Insome embodiments, the methods provided herein can reduce symptomsassociated with a skin condition (e.g., itchiness and/or inflammation).In some such embodiments, the compound provided herein is administeredtopically (e.g., as a topical cream, eyedrop, nose drop or nasal spray).In some such embodiments, the compound is a PI3K delta inhibitor (e.g.,a PI3K inhibitor that demonstrates greater inhibition of PI3K delta thanof other PI3K isoforms). In some embodiments, the PI3K delta inhibitorprevents mast cell degranulation.

As used herein, “skin condition” includes any inflammatory condition ofthe skin (e.g., eczema or dermatitis, e.g., contact dermatitis, atopicdermatitis, dermatitis herpetiformis, seborrheic dermatitis, nummulardermatitis, stasis dermatitis, perioral dermatitis), as well asaccompanying symptoms (e.g., skin rash, itchiness (pruritis), swelling(edema), hay fever, anaphalaxis). Frequently, such skin conditions arecaused by an allergen. As used herein, a “skin condition” also includes,e.g., skin rashes (e.g., allergic rashes, e.g., rashes resulting fromexposure to allergens such as poison ivy, poison oak, or poison sumac,or rashes caused by other diseases or conditions), insect bites, minorburns, sunburn, minor cuts, and scrapes. In some embodiments, thesymptom associated with inflammatory myopathy, or the skin condition orsymptom associated with the skin condition, is a skin rash or itchiness(pruritis) caused by a skin rash.

The skin condition (e.g., the skin rash) may be spontaneous, or it maybe induced, e.g., by exposure to an allergen (e.g., poison ivy, poisonoak, or poison sumac), drugs, food, insect bite, inhalants, emotionalstress, exposure to heat, exposure to cold, or exercise. In someembodiments, the skin condition is a skin rash (e.g., a pruritic rash,e.g., utricaria). In some embodiments, the skin condition is an insectbite. In some embodiments, the skin condition is associated with anotherdisease (e.g., an inflammatory myopathy, e.g., dermatomyositis).

In some embodiments, the subject (e.g., the subject in need of treatmentfor an inflammatory myopathy and/or a skin condition) exhibits anelevated level or elevated activity of IFN-a, TNF-α, IL-6, IL-8, IL-1,or a combination thereof. In certain embodiments, the subject exhibitsan elevated level of IFN-a. In some embodiments, treating (e.g.,decreasing or inhibiting) the inflammatory myopathy, or the skincondition, comprises inhibiting (e.g., decreasing a level of, ordecreasing a biological activity of) one or more of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-α, TNF-α, IL-6,IL-8, or IL-1 in the subject or in a sample derived from the subject. Insome embodiments, the method decreases a level of IFN-a in the subjector in a sample derived from the subject. In some embodiments, the levelof IFN-α, TNF-α, IL-6, IL-8, or IL-1 is the level assessed in a sampleof whole blood or PBMCs. In some embodiments, the level of IFN-α, TNF-α,IL-6, IL-8, or IL-1 is the level assessed in a sample obtained by a skinbiopsy or a muscle biopsy. In some embodiments, the sample is obtainedby a skin biopsy.

In one embodiment, provided herein is a method of treating, preventingand/or managing myositis. As used herein, “myositis” encompasses alltypes and manifestations of myositis. Examples include, but are notlimited to, myositis ossificans, fibromyositis, idiopathic inflammatorymyopathies, dermatomyositis, juvenile dermatomyositis, polymyositis,inclusion body myositis and pyomyositis. In one embodiment, the diseaseor disorder is dermatomyositis. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith myositis. Examples of the symptoms include, but are not limited to:muscle weakness; trouble lifting arms; trouble swallowing or breathing;muscle pain; muscle tenderness; fatigue; fever; lung problems;gastrointestinal ulcers; intestinal perforations; calcinosis under theskin; soreness; arthritis; weight loss; and rashes.

In one embodiment, provided herein is a method of treating, preventingand/or managing lupus. As used herein, “lupus” refers to all types andmanifestations of lupus. Examples include, but are not limited to,systemic lupus erythematosus; lupus nephritis; cutaneous manifestations(e.g., manifestations seen in cutaneous lupus erythematosus, e.g., askin lesion or rash); CNS lupus; cardiovascular, pulmonary, hepatic,hematological, gastrointestinal and musculoskeletal manifestations;neonatal lupus erythematosus; childhood systemic lupus erythematosus;drug-induced lupus erythematosus; anti-phospholipid syndrome; andcomplement deficiency syndromes resulting in lupus manifestations. Inone embodiment, the lupus is systemic lupus erythematosus (SLE),cutaneous lupus erythematosus (CLE), drug-induced lupus, or neonatallupus. In another embodiment, the lupus is a CLE, e.g., acute cutaneouslupus erythematosus (ACLE), subacute cutaneous lupus erythematosus(SCLE), intermittent cutaneous lupus erythematosus (also known as lupuserythematosus tumidus (LET)), or chronic cutaneous lupus. In someembodiments, the intermittent CLE is chronic discloid lupuserythematosus (CDLE) or lupus erythematosus profundus (LEP) (also knownas lupus erythematosus panniculitis). Types, symptoms, and pathogenesisof CLE are described, for example, in Wenzel et al. (2010), Lupus, 19,1020-1028.

In one embodiment, provided herein is a method of treating, preventingand/or managing Sjögren's syndrome. As used herein, “Sjögren's syndrome”refers to all types and manifestations of Sjögren's syndrome. Examplesinclude, but are not limited to, primary and secondary Sjögren'ssyndrome. Also provided herein is a method of treating, preventingand/or managing one or more symptoms associated with Sjögren's syndrome.Examples of the symptoms include, but are not limited to: dry eyes; drymouth; joint pain; swelling; stiffness; swollen salivary glands; skinrashes; dry skin; vaginal dryness; persistent dry cough; and prolongedfatigue.

In some embodiments, a symptom associated with the disease or disorderprovided herein is reduced by at least 10%, at least 20%, at least 30%,at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95% relative to a control level. The controllevel includes any appropriate control as known in the art. For example,the control level can be the pre-treatment level in the sample orsubject treated, or it can be the level in a control population (e.g.,the level in subjects who do not have the disease or disorder or thelevel in samples derived from subjects who do not have the disease ordisorder). In some embodiments, the decrease is statisticallysignificant, for example, as assessed using an appropriate parametric ornon-parametric statistical comparison.

Combination Therapy

In some embodiments, provided herein are methods for combinationtherapies in which an agent known to modulate other pathways, or othercomponents of the same pathway, or even overlapping sets of targetenzymes are used in combination with a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. In one aspect, such therapy includes, but is notlimited to, the combination of the subject compound withchemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

In one aspect, a compound as provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, orpharmaceutical compositions as provided herein, can presentsynergistic or additive efficacy when administered in combination withagents that inhibit IgE production or activity. Such combination canreduce the undesired effect of high level of IgE associated with the useof one or more PI3K-δ inhibitors, if such effect occurs. This can beparticularly useful in treatment of autoimmune and inflammatorydisorders (AILD) such as rheumatoid arthritis. Additionally, theadministration of PI3K-δ or PI3K-δ/γ inhibitors as provided herein incombination with inhibitors of mTOR can also exhibit synergy throughenhanced inhibition of the PI3K pathway.

In a separate but related aspect, provided herein is a combinationtreatment of a disease associated with PI3K-δ comprising administeringto a PI3K-δ inhibitor and an agent that inhibits IgE production oractivity. Other exemplary PI3K-δ inhibitors are applicable for thiscombination and they are described, e.g., U.S. Pat. No. 6,800,620. Suchcombination treatment is particularly useful for treating autoimmune andinflammatory diseases (AIID) including, but not limited to rheumatoidarthritis.

Agents that inhibit IgE production are known in the art and theyinclude, but are not limited to, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

For treatment of autoimmune diseases, a compound as provided herein, ora pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,can be used in combination with commonly prescribed drugs including, butnot limited to Enbrel®, Remicade®, Humira®, Avonex®, and Rebif®. Fortreatment of respiratory diseases, the subject compounds orpharmaceutical compositions can be administered in combination withcommonly prescribed drugs including, but not limited to Xolair®,Advair®, Singulair®, and Spiriva®.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be formulated oradministered in conjunction with other agents that act to relieve thesymptoms of inflammatory conditions such as encephalomyelitis, asthma,and the other diseases described herein. These agents includenon-steroidal anti-inflammatory drugs (NSAIDs), e.g., acetylsalicylicacid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc.Corticosteroids are used to reduce inflammation and suppress activity ofthe immune system. An exemplary drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) can also be usedin some individuals with lupus. They can be prescribed for skin andjoint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide(Cytoxan) suppress inflammation and tend to suppress the immune system.Other agents, e.g., methotrexate and cyclosporin are used to control thesymptoms of lupus. Anticoagulants are employed to prevent blood fromclotting rapidly. They range from aspirin at very low dose whichprevents platelets from sticking, to heparin/coumadin. Other compoundsused in the treatment of lupus include belimumab (Benlysta®).

In another aspect, provided herein is a pharmaceutical composition forinhibiting abnormal cell growth in a subject which comprises an amountof a compound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, in combinationwith an amount of an anti-cancer agent (e.g., a chemotherapeutic agent).Many chemotherapeutics are presently known in the art and can be used incombination with the compounds as provided herein.

In some embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib),Casodex (bicalutamide), Iressa®, and Adriamycin as well as a host ofchemotherapeutic agents. Non-limiting examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclosphosphamide(CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; BTK inhibitorssuch as ibrutinib (PCI-32765) and AVL-292; HDAC inhibitors such asvorinostat, romidepsin, panobinostat, valproic acid, belinostat,mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat,CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215 andkevetrin; JAKISTAT inhibitors such as lestaurtinib, tofacitinib,ruxolitinib, pacritinib, CYT387, baricitinib, fostamatinib, GLPG0636,TG101348, INCB16562 and AZDI480; nitrogen mustards such as bedamustine,chlorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; antibiotics such asaclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pralatrexate, pteropterin, trimetrexate; purine analogssuch as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France) and ABRAXANE®(paclitaxel protein-bound particles); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) of any of the above.Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO). Where desired, the compounds orpharmaceutical composition as provided herein can be used in combinationwith commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®,Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE,Abagovomab, Acridine carboxamide, Adecatumumab,17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide,Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenicherbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine,BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine,CBV (chemotherapy), Calyculin, Crizotinib, cell-cycle nonspecificantineoplastic agents, Dichloroacetic acid, Discodermolide,Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan,Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen,IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar,Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide,Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1,Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod,Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V,Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel,Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,Uramustine, Vadimezan, Vinflunine, ZD6126, and Zosuquidar.

In some embodiments, the chemotherapeutic is selected from hedgehoginhibitors including, but not limited to 1P1-926 (See U.S. Pat. No.7,812,164). Other suitable hedgehog inhibitors include, for example,those described and provided in U.S. Pat. No. 7,230,004, U.S. PatentApplication Publication No. 2008/0293754, U.S. Patent ApplicationPublication No. 2008/0287420, and U.S. Patent Application PublicationNo. 2008/0293755, the entire disclosures of which are incorporated byreference herein. Examples of other suitable hedgehog inhibitors includethose described in U.S. Patent Application Publication Nos. US2002/0006931, US 2007/0021493 and US 2007/0060546, and InternationalApplication Publication Nos. WO 2001/19800, WO 2001/26644, WO2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354. Additional examples of hedgehog inhibitors include, but arenot limited to, GDC-0449 (also known as RG3616 or vismodegib) describedin, e.g., Von Hoff D. et al., N. Engl. J. Med. 2009; 361(12):1164-72;Robarge K. D. et al., Bioorg Med Chem Lett. 2009; 19(19):5576-81; Yauch,R. L. et al. (2009) Science 326: 572-574; Sciencexpress: 1-3(10.1126/science.1179386); Rudin, C. et al. (2009) New England J ofMedicine 361-366 (10.1056/nejma0902903); BMS-833923 (also known asXL139) described in, e.g., in Siu L. et al., J. Clin. Oncol. 2010;28:15s (suppl; abstr 2501); and National Institute of Health ClinicalTrial Identifier No. NCT006701891; LDE-225 described, e.g., in Pan S. etal., ACS Med. Chem. Lett., 2010; 1(3): 130-134; LEQ-506 described, e.g.,in National Institute of Health Clinical Trial Identifier No.NCT01106508; PF-04449913 described, e.g., in National Institute ofHealth Clinical Trial Identifier No. NCT00953758; Hedgehog pathwayantagonists provided in U.S. Patent Application Publication No.2010/0286114; SMOi2-17 described, e.g., U.S. Patent ApplicationPublication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., inRominger C. M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005;1-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med. Chem. Lett. 2010; 20(12):3618-22.

Other chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamideand bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalentsuch as nanoparticle albumin-bound paclitaxel (Abraxane),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonucleotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine,doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C), cytosine arabinoside, andfludarabine), purine analogs (e.g. mercaptopurine and Thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin),imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g.,axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),oblimersen, gemcitabine, caminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide,caminomycin-aminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar(tositumomab)).

In some embodiments, the chemotherapeutic is selected from HSP90inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g.,a benzoquinone or hygroquinone ansamycin HSP90 inhibitor (e.g., IPI-493and/or IPI-504). Non-limiting examples of HSP90 inhibitors includeIPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010),BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009),SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG,CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159,CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3Kinhibitors (e.g., including those PI3K inhibitors provided herein andthose PI3K inhibitors not provided herein). In some embodiment, the PI3Kinhibitor is an inhibitor of delta and gamma isoforms of PI3K. In someembodiments, the PI3K inhibitor is an inhibitor of alpha isoforms ofPI3K. In other embodiments, the PI3K inhibitor is an inhibitor of one ormore alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3Kinhibitors that can be used in combination are described in, e.g., WO09/088,990, WO 09/088,086, WO 2011/008302, WO 2010/036380, WO2010/006086, WO 09/114,870, WO 05/113556; US 2009/0312310, and US2011/0046165. Additional PI3K inhibitors that can be used in combinationwith the pharmaceutical compositions, include but are not limited to,AMG-319, GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL499, XL756,XL147, PF-46915032, BKM 120, CAL-101 (GS-1101), CAL 263, SF1126, PX-886,and a dual PI3K inhibitor (e.g., Novartis BEZ235). In one embodiment,the PI3K inhibitor is an isoquinolinone.

In some embodiments, provided herein is a method for using the acompound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the subject. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound as provided herein in this combination therapy can bedetermined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner as provided herein include both solids and liquids. Byway of non-limiting example, the radiation source can be a radionuclide,such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solidsource, or other radionuclides that emit photons, beta particles, gammaradiation, or other therapeutic rays. The radioactive material can alsobe a fluid made from any solution of radionuclide(s), e.g., a solutionof I-125 or I-131, or a radioactive fluid can be produced using a slurryof a suitable fluid containing small particles of solid radionuclides,such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in agel or radioactive micro spheres.

Without being limited by any theory, the compounds as provided herein,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,can render abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, provided herein is a method for sensitizing abnormal cellsin a subject to treatment with radiation which comprises administeringto the subject an amount of a compound as provided herein orpharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, which amount is effective is sensitizing abnormalcells to treatment with radiation. The amount of the compound used inthis method can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used incombination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound as provided herein and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/1B98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. In some embodiments, MMP-2 and MMP-9inhibitors are those that have little or no activity inhibiting MMP-1.Other embodiments include those that selectively inhibit MMP-2 and/orAMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1,MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-II, MMP-12, andMMP-13). Some non-limiting examples of MMP inhibitors are AG-3340, RO32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

In some embodiments, provided herein is a method of and/or apharmaceutical composition for treating a cardiovascular disease in asubject which comprises an amount of a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, and an amount of one or more therapeutic agentsuse for the treatment of cardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings. Moreover, a coating can be used to effect therapeutic deliveryfocally within the vessel wall. By incorporation of the active agent ina swellable polymer, the active agent will be released upon swelling ofthe polymer.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

Medicaments which can be administered in conjunction with the compoundsas provided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, include anysuitable drugs usefully delivered by inhalation for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g. cromoglycate,ketotifen or nedocromil; anti-infectives, e.g., cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments can be usedin the form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) to optimize theactivity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude, but are not limited to, agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated herein include drugs used forcontrol of gastric acidity, agents for the treatment of peptic ulcers,agents for the treatment of gastroesophageal reflux disease, prokineticagents, antiemetics, agents used in irritable bowel syndrome, agentsused for diarrhea, agents used for constipation, agents used forinflammatory bowel disease, agents used for biliary disease, agents usedfor pancreatic disease. Therapeutic agents include, but are not limitedto, those used to treat protozoan infections, drugs used to treatMalaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/orLeishmaniasis, and/or drugs used in the chemotherapy of helminthiasis.Other therapeutic agents include, but are not limited to, antimicrobialagents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, andagents for urinary tract infections, penicillins, cephalosporins, andother, β-Lactam antibiotics, an agent containing an aminoglycoside,protein synthesis inhibitors, drugs used in the chemotherapy oftuberculosis, mycobacterium avium complex disease, and leprosy,antifungal agents, antiviral agents including nonretroviral agents andantiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one can combine a compound as providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or pharmaceuticalcompositions as provided herein, with sorafenib and/or avastin. Fortreating an endometrial disorder, one can combine a compound as providedherein with doxorubincin, taxotere (taxol), and/or cisplatin(carboplatin). For treating ovarian cancer, one can combine a compoundas provided herein with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one can combinea compound as provided herein with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one can combine a compound as provided herein with taxotere (taxol),gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/or avastin.

In some embodiments, the disorder to be treated, prevented and/ormanaged is hematological cancer, e.g., lymphoma (e.g., T-cell lymphoma;NHL), myeloma (e.g., multiple myeloma), and leukemia (e.g., CLL), and acompound provided herein is used in combination with: HDAC inhibitorssuch as vorinostat and romidepsin; mTOR inhibitors such as everolmus;anti-folates such as pralatrexate; nitrogen mustard such asbendamustine; gemcitabine, optionally in further combination withoxaliplatin; rituximab.cyclophosphamide combination; PI3K inhibitorssuch as GS-1101, XL 499, GDC-0941, and AMG-319; or BTK inhibitors suchas ibrutinib and AVL-292.

In certain embodiments, wherein inflammation (e.g., arthritis, asthma)is treated, prevented and/or managed, a compound provided herein can becombined with, for example: PI3K inhibitors such as GS-1101, XL 499,GDC-0941, and AMG-319; BTK inhibitors such as ibrutinib and AVL-292; JAKinhibitors such as tofacitinib, fostamatinib, and GLPG0636.

In certain embodiments wherein asthma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:beta 2-agonists such as, but not limited to, albuterol (Proventil®, orVentolin®), salmeterol (Serevent®), formoterol (Foradil®),metaproterenol (Alupent®), pirbuterol (MaxAir®), and terbutalinesulfate; corticosteroids such as, but not limited to, budesonidePulmicort®), flunisolide (e.g., AeroBid Oral Aerosol Inhaler® orNasalide Nasal Aerosol®), fluticasone (e.g., Flonase® or Flovent®) andtriamcinolone (e.g., Azmacort®); mast cell stabilizers such as cromolynsodium (e.g., Intal® or Nasalcrom®) and nedocromil (e.g., Tilade®);xanthine derivatives such as, but not limited to, theophylline (e.g.,Aminophyllin®, Theo-24® or Theolair®); leukotriene receptor antagonistssuch as, but are not limited to, zafirlukast (Accolate®), montelukast(Singulair®), and zileuton (Zyflo®); and adrenergic agonists such as,but are not limited to, epinephrine (Adrenalin®, Bronitin®, EpiPen® orPrimatene Mist®).

In certain embodiments wherein arthritis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:TNF antagonist (e.g., a TNF antibody or fragment, a soluble TNF receptoror fragment, fusion proteins thereof, or a small molecule TNFantagonist); an antirheumatic (e.g., methotrexate, auranofin,aurothioglucose, azathioprine, etanercept, gold sodium thiomalate,hydroxychloroquine sulfate, leflunomide, sulfasalzine); a musclerelaxant; a narcotic; a non-steroid anti-inflammatory drug (NSAID); ananalgesic; an anesthetic; a sedative; a local anesthetic; aneuromuscular blocker; an antimicrobial (e.g., an aminoglycoside, anantifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin,a fluoroquinolone, a macrolide, a penicillin, a sulfonamide, atetracycline, another antimicrobial); an antipsoriatic; acorticosteroid; an anabolic steroid; a cytokine or a cytokineantagonist.

In certain embodiments wherein psoriasis is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:budesonide, epidermal growth factor, corticosteroids, cyclosporine,sulfasalazine, aminosalicylates, 6-mercaptopurine, azathioprine,metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine,balsalazide, antioxidants, thromboxane inhibitors, IL-1 receptorantagonists, anti-IL-1β monoclonal antibodies, anti-IL-6 monoclonalantibodies, growth factors, elastase inhibitors, pyridinyl-imidazolecompounds, antibodies or agonists of TNF, LT, IL-1, IL-2, IL-6, IL-7,IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies ofCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, prednisolone,phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents,complement inhibitors, adrenergic agents, IRAK, NIK, IKK, p38, MAPkinase inhibitors, IL-1β converting enzyme inhibitors, TNFα convertingenzyme inhibitors, T-cell signaling inhibitors, metalloproteinaseinhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensinconverting enzyme inhibitors, soluble cytokine receptors, soluble p55TNF receptor, soluble p75 TNF receptor, sIL-1RI, sILo-1RII, sIL-6R,anti-inflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and TGFβ.

In certain embodiments wherein fibrosis or fibrotic condition of thebone marrow is treated, prevented and/or managed, a compound providedherein can be combined with, for example, a Jak2 inhibitor (including,but not limited to, INCB018424, XL019, TG101348, or TG101209), animmunomodulator, e.g., an IMID® (including, but not limited tothalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen,erythropoietic stimulating agents, prednisone, danazol, HDAC inhibitors,or other agents or therapeutic modalities (e.g., stem cell transplants,or radiation).

In certain embodiments wherein fibrosis or fibrotic condition of theheart is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, eplerenone, furosemide, pycnogenol,spironolactone, TcNC100692, torasemide (e.g., prolonged release form oftorasemide), or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thekidney is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, cyclosporine, cyclosporine A,daclizumab, everolimus, gadofoveset trisodium (ABLAVAR®), imatinibmesylate (GLEEVEC®), matinib mesylate, methotrexate, mycophenolatemofetil, prednisone, sirolimus, spironolactone, STX-100, tamoxifen,TheraCLEC™, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theskin is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, Bosentan (Tracleer), p144,pentoxifylline; pirfenidone; pravastatin, STI571, Vitamin E, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thegastrointestinal system is treated, prevented and/or managed, a compoundprovided herein can be combined with, for example, ALTU-135, bucelipasealfa (INN), DCHI1020, EUR-1008 (ZENPEP™), ibuprofen, Lym-X-Sorb powder,pancrease MT, pancrelipase (e.g., pancrelipase delayed release), pentadecanoic acid (PA), repaglinide, TheraCLECT™, triheptadecanoin (THA),ULTRASE MT20, ursodiol, or combinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of thelung is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, 18-FDG, AB0024, ACT-064992(macitentan), aerosol interferon-gamma, aerosolized human plasma-derivedalpha-1 antitrypsin, alpha1-proteinase inhibitor, ambrisentan, amikacin,amiloride, amitriptyline, anti-pseudomonas IgY gargle, ARIKACE™ AUREXIS®(tefibazumab), AZAPRED, azathioprine, azithromycin, azithromycin, AZLI,aztreonam lysine, BIBF1120, Bio-25 probiotic, bosentan, Bramitob®,calfactant aerosol, captopril, CC-930, ceftazidime, ceftazidime,cholecalciferol (Vitamin D3), ciprofloxacin (CIPRO®, BAYQ3939), CNTO888, colistin CF, combined Plasma Exchange (PEX), rituximab, andcorticosteroids, cyclophosphamide, dapsone, dasatinib, denufosoltetrasodium (INS37217), dornase alfa (PULMOZYME®), EPI-hNE4,erythromycin, etanercept, FG-3019, fluticasone, FT1, GC1008, GS-9411,hypertonic saline, ibuprofen, iloprost inhalation, imatinib mesylate(GLEEVEC®), inhaled sodium bicarbonate, inhaled sodium pyruvate,interferon gamma-1b, interferon-alpha lozenges, isotonic saline, IW001,KB001, losartan, lucinactant, mannitol, meropenem, meropenem infusion,miglustat, minocycline, Moli1901, MP-376 (levofloxacin solution forinhalation), mucoid exopolysaccharide P. aeruginosa immune globulin IV,mycophenolate mofetil, n-acetylcysteine, N-acetylcysteine (NAC), NaCl6%, nitric oxide for inhalation, obramycin, octreotide, oligoG CF-5/20,Omalizumab, pioglitazone, piperacillin-tazobactam, pirfenidone,pomalidomide (CC-4047), prednisone, prevastatin, PRM-151, QAX576,rhDNAse, SB656933, SB-656933-AAA, sildenafil, tamoxifen, technetium[Tc-99 m]sulfur colloid and Indium [In-111] DTPA, tetrathiomolybdate,thalidomide, ticarcillin-clavulanate, tiotropium bromide, tiotropiumRESPIMAT® inhaler, tobramycin (GERNEBCIN®), treprostinil, uridine,valganciclovir (VALCYTE®), vardenafil, vitamin D3, xylitol, zileuton, orcombinations thereof.

In certain embodiments wherein fibrosis or fibrotic condition of theliver is treated, prevented and/or managed, a compound provided hereincan be combined with, for example, adefovir dipivoxil, candesartan,colchicine, combined ATG, mycophenolate mofetil, and tacrolimus,combined cyclosporine microemulsion and tacrolimus, elastometry,everolimus, FG-3019, Fuzheng Huayu, G1262570, glycyrrhizin (monoammoniumglycyrrhizinate, glycine, L-cysteine monohydrochloride), interferongamma-1b, irbesartan, losartan, oltipraz, ORAL IMPACT®, peginterferonalfa-2a, combined peginterferon alfa-2a and ribavirin, peginterferonalfa-2b (SCH 54031), combined peginterferon alpha-2b and ribavirin,praziquantel, prazosin, raltegravir, ribavirin (REBETOL®, SCH 18908),ritonavir-boosted protease inhibitor, pentoxyphilline, tacrolimus,tauroursodeoxycholic acid, tocopherol, ursodiol, warfarin, orcombinations thereof.

In certain embodiments wherein cystic fibrosis is treated, preventedand/or managed, a compound provided herein can be combined with, forexample, 552-02, 5-methyltetrahydrofolate and vitamin B12, Ad5-CB-CFTR,Adeno-associated virus-CFTR vector, albuterol, alendronate, alphatocopherol plus ascorbic acid, amiloride HCl, aquADEK™, ataluren(PTC124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin(clarithromycin), BIIL 283 BS (amelubent), buprofen, calcium carbonate,ceftazidime, cholecalciferol, choline supplementation, CPX, cysticfibrosis transmembrane conductance regulator, DHA-rich supplement,digitoxin, cocosahexaenoic acid (DHA), doxycycline, ECGC, ecombinanthuman IGF-1, educed glutathione sodium salt, ergocalciferol (vitaminD2), fluorometholone, gadobutrol (GADOVIST®, BAY86-4875), gentamicin,ghrelin, glargine, glutamine, growth hormone, GS-9411, H5.001CBCFTR,human recombinant growth hormone, hydroxychloroquine, hyperbaric oxygen,hypertonic saline, IH636 grape seed proanthocyanidin extract, insulin,interferon gamma-1b, IoGen (molecular iodine), iosartan potassium,isotonic saline, itraconazole, IV gallium nitrate (GANITE®) infusion,ketorolac acetate, lansoprazole, L-arginine, linezolid, lubiprostone,meropenem, miglustat, MP-376 (levofloxacin solution for inhalation),normal saline IV, Nutropin AQ, omega-3 triglycerides, pGM169/GL67A,pGT-1 gene lipid complex, pioglitazone, PTC124, QAU145, salmeterol,SB656933, SB656933, simvastatin, sitagliptin, sodium 4-phenylbutyrate,standardized turmeric root extract, tgAAVCF, TNF blocker, TOBI,tobramycin, tocotrienol, unconjugated Isoflavones 100, vitamin: cholinebitartrate (2-hydroxyethyl) trimethylammonium salt 1:1, VX-770, VX-809,Zinc acetate, or combinations thereof.

In some embodiments, a compound provided herein is administered incombination with an agent that inhibits IgE production or activity. Insome embodiments, the PI3K inhibitor (e.g., PI3δ inhibitor) isadministered in combination with an inhibitor of mTOR. Agents thatinhibit IgE production are known in the art and they include but are notlimited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

In certain embodiments wherein scleroderma is treated, prevented and/ormanaged, a compound provided herein can be combined with, for example:an immunosuppressant (e.g., methotrexate, azathioprine (Imuran®),cyclosporine, mycophenolate mofetil (Cellcepte), and cyclophosphamide(Cytoxan®)); T-cell-directed therapy (e.g., halofuginone, basiliximab,alemtuzumab, abatacept, rapamycin); B-cell directed therapy (e.g.,rituximab); autologous hematopoietic stem cell transplantation; achemokine ligand receptor antagonist (e.g., an agent that targets theCXCL12/CSCR4 axis (e.g., AMD3100)); a DNA methylation inhibitor (e.g.,5-azacytidine); a histone dactylase inhibitor (e.g., trichostatin A); astatin (e.g., atorvastatin, simvastatin, pravastatin); an endothelinreceptor antagonist (e.g., Bosentan®); a phosphodiesterase type Vinhibitor (e.g., Sildenafil®); a prostacyclin analog (e.g.,trepostinil); an inhibitor of cytokine synthesis and/or signaling (e.g.,Imatinib mesylate, Rosiglitazone, rapamycin, antitransforming growthfactor β1 (anti-TGFβ1) antibody, mycophenolate mofetil, an anti-IL-6antibody (e.g., tocilizumab)); corticosteroids; nonsteroidalanti-inflammatory drugs; light therapy; and blood pressure medications(e.g., ACE inhibitors).

In certain embodiments wherein inflammatory myopathies are treated,prevented and/or managed, a compound provided herein can be combinedwith, for example: topical creams or ointments (e.g., topicalcorticosteroids, tacrolimus, pimecrolimus); cyclosporine (e.g., topicalcyclosporine); an anti-interferon therapy, e.g., AGS-009, Rontalizumab(rhuMAb IFNalpha), Vitamin D3, Sifalimumab (MEDI-545), AMG 811, IFNαKinoid, or CEP33457. In some embodiments, the other therapy is an IFN-αtherapy, e.g., AGS-009, Rontalizumab, Vitamin D3, Sifalimumab (MEDI-545)or IFNα Kinoid; corticosteroids such as prednisone (e.g., oralprednisone); immunosuppressive therapies such as methotrexate (Trexall®,Methotrexate®, Rheumatrex®), azathioprine (Azasan®, Imuran®),intravenous immunoglobulin, tacrolimus (Prograf®), pimecrolimus,cyclophosphamide (Cytoxan®), and cyclosporine (Gengraf®, Neoral®,Sandimmune®); anti-malarial agents such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®); total body irradiation;rituximab (Rituxan®); TNF inhibitors (e.g., etanercept (Enbrel®),infliximab (Remicade®)); AGS-009; Rontalizumab (rhuMAb IFNalpha);Vitamin D3; Sifalimumab (MEDI-545); AMG 811; IFNα Kinoid; CEP33457;agents that inhibit IgE production such as TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2;agents that inhibit IgE activity such as anti-IgE antibodies (e.g.,Omalizumab and TNX-90); and additional therapies such as physicaltherapy, exercise, rest, speech therapy, sun avoidance, heat therapy,and surgery.

In certain embodiments wherein myositis (e.g., dermatomysitis) istreated, prevented and/or managed, a compound provided herein can becombined with, for example: corticosteroids; corticosteroid sparingagents such as, but not limited to, azathioprine and methotrexate;intravenous immunoglobulin; immunosuppressive agents such as, but notlimited to, tacrolimus, cyclophosphamide and cyclosporine; rituximab;TNFα inhibitors such as, but not limited to, etanercept and infliximab;growth hormone; growth hormone secretagogues such as, but not limitedto, MK-0677, L-162752, L-163022, NN703 ipamorelin, hexarelin, GPA-748(KP102, GHRP-2), and LY444711 (Eli Lilly); other growth hormone releasestimulators such as, but not limited to, Geref, GHRH (1-44), Somatorelin(GRF 1-44), ThGRF genotropin, L-DOPA, glucagon, and vasopressin; andinsulin-like growth factor.

In certain embodiments wherein Sjögren's syndrome is treated, preventedand/or managed, a compound provided herein can be combined with, forexample: pilocarpine; cevimeline; nonsteroidal anti-inflammatory drugs;arthritis medications; antifungal agents; cyclosporine;hydroxychloroquine; prednisone; azathioprine; and cyclophamide.

Further therapeutic agents that can be combined with a subject compoundcan be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents provided herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments, the compounds asprovided herein will be co-administered with other agents as describedabove. When used in combination therapy, the compounds described hereincan be administered with the second agent simultaneously or separately.This administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.That is, a compound described herein and any of the agents describedabove can be formulated together in the same dosage form andadministered simultaneously. Alternatively, a compound as providedherein and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound as provided herein canbe administered just followed by and any of the agents described above,or vice versa. In the separate administration protocol, a compound asprovided herein and any of the agents described above can beadministered a few minutes apart, or a few hours apart, or a few daysapart.

Administration of the compounds as provided herein can be effected byany method that enables delivery of the compounds to the site of action.An effective amount of a compound as provided herein can be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

When a compound as provided herein is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound as provided herein, unit dose formsof the agent and the compound as provided herein can be adjustedaccordingly.

The examples and preparations provided below further illustrate andexemplify the compounds as disclosed herein and methods of preparingsuch compounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations. In the following examples molecules with asingle chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers can be obtained by methods known to thoseskilled in the art.

EXAMPLES

Chemical Examples

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period that is, for example, about 1 to about24 hours; reactions left to run overnight in some embodiments canaverage a period of about 16 hours.

The terms “solvent,” “organic solvent,” or “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation proceduresare given by reference to the examples hereinbelow. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the non-limiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer can besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Aldrich Chemical Company (Milwaukee, Wis.) or can be readilyprepared by those skilled in the art using commonly employed syntheticmethodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein.

General Synthetic Methods

The compounds herein being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodiments,and are not intended.

(i) General Methods for the Synthesis of Cl-W_(d) and TsO-W_(d)Heterocycles:

Method A

General Conditions for the Preparation of4-chloropyrido[3,2-d]pyrimidine:

3-Aminopicolinic acid (A-1) (30 g, 217 mmol, 1.0 eq) is suspended informamide (75 mL, 1.88 mol, 8.66 eq). The resulting mixture is stirredat 140° C. for 1 h and at 170° C. for 1 h and then at 180° C. for anadditional 1 h. The mixture is cooled to RT and filtered. The filtercake is washed with water, and dried in vacuo to afford the product,pyrido[3,2-d]pyrimidin-4-ol (A-2).

To a stirred solution of pyrido[3,2-d]pyrimidin-4-ol (A-2) (16 g, 109mmol, 1.0 eq) and DMF (0.4 mL) in DCM (200 mL) at RT, oxalyl chloride(23.2 mL, 272 mmol, 2.5 eq) is added dropwise (over 5 min) and theresulting mixture is stirred at reflux overnight. The mixture is allowedto cool to RT and concentrated in vacuo. The residue is diluted withwater (200 mL), neutralized with saturated aqueous NaHCO₃ solution below10° C. to adjust the pH to 8-9 and then extracted with ethyl acetate(4×100 mL). The combined organic layers are washed with brine, driedover Na₂SO₄ and filtered. The filtrate is concentrated in vacuo. Theresidue is purified by flash column chromatography on silica gel (16-50%ethyl acetate-petro ether) to afford the product,4-chloropyrido[3,2-d]pyrimidine (A-3).

Method B

General Method for Synthesis of 2,4-dichloropyrido[3,2-d]pyrimidines:

3-Aminopicolinic acid (A-1) (1.0 g, 7.24 mmol, 1.0 eq), potassiumcyanate (2.94 g, 36.2 mmol, 5.0 eq) and ammonium chloride (3.87 g, 72.4mmol, 10.0 eq) are suspended in water (40 mL). The slurry is heated to160° C. and mixed manually for 2 h as water vapour is expelled from thereaction vessel. The reaction temperature is then increased to 200° C.and stirred for 40 min. After cooling to 90° C., hot water is added andthen the mixture is allowed to cool to RT. The mixture is acidified withconcentrated HCl to adjust pH to 3-4. The precipitate is collected byfiltration, rinsed with water (2×10 mL) and dried in vacuo to afford theproduct, pyrido[3,2-d]pyrimidine-2,4-diol (B-1).

A mixture of pyrido[3,2-d]pyrimidine-2,4-diol (B-1) (360 mg, 2.21 mmol,1.0 eq) and PCl₅ (1.84 g, 8.83 mmol, 8.0 eq) in POCl₃ (20 mL) is stirredat reflux for 8 h. An additional amount of PCl₅ (1.84 g, 8.83 mmol, 8.0eq) and POCl₃ (20 mL) are added, and the resulting mixture is stirred atreflux for 16 h. After cooling to RT, the mixture is concentrated invacuo and the residue is poured into ice-water. The mixture isneutralized with saturated Na₃CO₃ to adjust the pH to 8-9, and thenextracted with DCM (3×20 mL). The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo and the residue is purified by column chromatography on silicagel (10-12% ethyl acetate/petro ether) to afford the product,2,4-dichloropyrido[3,2-d]pyrimidine (B-2).

Method C

General Method for Synthesis of4-chloro-1,5-naphthyridine-3-carbonitriles:

A mixture of pyridin-3-amine (C-1) (10.0 g, 106.3 mmol, 1.0 eq) and(E)-ethyl 2-cyano-3-ethoxyacrylate (C-2) (21.5 g, 127 mmol, 1.2 eq) intoluene (40 mL) is stirred at reflux under argon for 5 h and thenallowed to cool to RT. The precipitate is collected by filtration,rinsed with a mixture of petroether and ethyl acetate (v/v=2:1, 3×10mL), and then dried in vacuo to afford the product, ethyl2-cyano-3-(pyridin-3-ylamino)acrylate (C-3).

The mixture of ethyl 2-cyano-3-(pyridin-3-ylamino)acrylate (C-3) (2.0 g,9.26 mmol, 1.0 eq) in Dowtherm A (48 mL) is stirred at 260° C. for 5 h.The mixture is cooled to RT and poured into a mixture of MeOH and DCM(v/v=1:2, 20 mL). The precipitate is filtered, rinsed with DCM, anddried in vacuo to afford the product,4-hydroxy-1,5-naphthyridine-3-carbonitrile (C-4).

A mixture of 4-hydroxy-1,5-naphthyridine-3-carbonitrile (C-4) (2.0 g,11.7 mmol, 1.0 eq) in phosphoroxychloride (40 mL, 424 mol, 36.2 eq) isstirred at reflux for 3 h. The mixture is cooled to RT and concentratedin vacuo. The residue is poured into ice-water (50 mL) and neutralizedwith saturated aqueous NaHCO₁ solution to adjust the pH to 8 whilekeeping the temperature below 5° C. The mixture is extracted with DCM(3×50 mL). The combined organic layer is washed with brine, dried overNa₂SO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is purified by flash column chromatography on silica gel (1.25%MeOH-DCM) to afford the product,4-chloro-1,5-naphthyridine-3-carbonitrile (C-5).

Method D

General Method for Synthesis of 4-chloro-1,5-naphthyridines:

To a mixture of pyridin-3-amine (C-1) (10.0 g, 106.3 mmol, 1.0 eq) inDCM (100 mL) at 0° C., m-chloroperoxybenzoic acid (22.0 g, 128 mmol, 1.2eq) is added in portions (over 15 min). The resulting mixture is allowedto warm to RT and then stirred at RT for 2 h. The reaction is quenchedwith water (100 mL). The organic phase is separated and the aqueouslayer is extracted with DCM (2×100 mL). The resulting aqueous phase isneutralized with concentrated HCl to adjust the pH to 2-3. To thismixture, 1,4-dioxane (100 mL) is added and the resulting mixture isconcentrated in vacuo to afford the product, 3-aminopyridine-1-oxidehydrochloride (D-1).

A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (D-2) (10.0 g, 70 mmol,1.0 eq) in trimethyl orthoformate (100 mL, 365 mmol, 5.0 eq) is stirredat reflux for 3 h. The resulting mixture is cooled to RT andconcentrated in vacuo. The residue is triturated with diethyl ether andthen filtered. The filter cake is washed with cooled diethyl ether anddried in vacuo to afford the product,5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (D-3).

To a mixture of 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(D-3) (7.6 g, 41.0 mmol, 1.0 eq) and 3-aminopyridine-1-oxidehydrochloride (D-1) (6.0 g, 41.0 mmol, 1.0 eq) in isopropanol (20 mL),N,N-diisopropylethylamine (7.2 mL, 53 mmol, 1.3 eq) is added and theresulting mixture is stirred at 90° C. for 20 min. The mixture isallowed to cool to RT and then poured into ice-water (50 mL). Theprecipitate is collected by filtration, rinsed with isopropanol (2×10mL) and diethyl ether (2×10 mL), and then dried in vacuo to afford theproduct, 2,2-dimethyl-5-((pyridin-1-oxide3-ylamino)methylene)-1,3-dioxane-4,6-dione (D-4).

The mixture of 2,2-dimethyl-5-((pyridin-1-oxide3-ylamino)methylene)-1,3-dioxane-4,6-dione (D-4) (5.1 g, 19.3 mmol, 1.0eq) in Dowtherm A (48 mL) is stirred at 260° C. for 5-10 min. Themixture is allowed to cool to RT and then diluted with petroleum ether.The precipitate is filtered, rinsed with petroleum ether, and dried invacuo to afford the product, 1,5-naphthyridin-5-oxide 4-ol (D-5).

To a solution of 1,5-naphthyridin-5-oxide 4-01 (D-5) (330 mg, 2.0 mmol,1.0 eq) in acetic acid (12 mL) and pyridine (2.5 mL) at RT, iron powder(456 mg, 8.15 mmol, 4.0 eq) is added in portions (over 10 min) and theresulting mixture is stirred for 2 h. The mixture is filtered and thesolid is rinsed with acetic acid. The filtrate is concentrated in vacuo.The residue is triturated with acetone and then filtered. The filtercake is rinsed with acetone and dried in vacuo to afford the product,1,5-naphthyridin-4-ol acetic acid salt (D-6).

A mixture of 1,5-naphthyridin-4-ol acetic acid salt (D-6) (800 mg, 3.0mmol, 1.0 eq) in phosphoroxychloride (5 mL, 53 mol, 17.6 eq) is stirredat 110° C. for 30 min, cooled to RT and then concentrated in vacuo. Theresidue is poured into ice-water (50 mL) and neutralized with saturatedaqueous NaHCO₃ solution to adjust the pH to 8-9 while keeping thetemperature below 5° C. The mixture is stirred at RT for 30 min and thenextracted with DCM (3×40 mL). The combined organic layers are washedwith brine, dried over Na₃SO₄ and filtered. The filtrate is concentratedin vacuo and the residue is purified by flash column chromatography onsilica gel (1-2% MeOH-DCM) to afford the product,4-chloro-1,5-naphthyridine (D-7).

Method Z

General Method for Synthesis of7-chloropyrazolo[1,5-a]pyrimidin-5-amine:

A solution of ethyl 2-cyanoacetate (100 mL, 94 mmol) in chloroform (100mL) and ethanol (6.5 mL) is bubbled with HCl at −10° for 4 h. Thereaction mixture is allowed to warm to RT slowly and then stirred at RTovernight. The mixture is concentrated in vacuo to remove the solvent.The residue is suspended in diethyl ether (100 mL) and stirred for 30min. The resulting solid is collected by filtration and rinsed withdiethyl ether to afford ethyl 3-ethoxy-3-iminopropanoate hydrochloride(Z-1) as a white solid.

Sodium bicarbonate (3.9 g, 46.2 mmol) is added in small portions to amixture of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-1) (8.6 g,44.0 mmol) in crushed ice (100 g) and ethyl acetate (50 mL) until the pHvalue reaches 8-9. The organic layer is separated and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The combined organic layersare dried over anhydrous MgSO₄ and filtered. The filtrate isconcentrated in vacuo to afford a colourless oil which is added to asolution of 1H-pyrazol-5-amine (3.65 g, 44.0 mmol) in ethanol (100 mL).The resulting mixture is then degassed and backfilled with argon (threecycles) and stirred at reflux overnight. The mixture is then filteredwhile it was still warm. The solid is rinsed with cold ethanol (25 mL)and ether (2×25 mL), and then dried in vacuo to afford5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2).

A solution of 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2) (1.5 g, 10mmol) in phosphoryl chloride (45 mL) is stirred at reflux overnight. Thereaction mixture is allowed to cool to RT and concentrated in vacuo. Theresidue is then dissolved in ice-water (25 mL) and the resulting mixtureis neutralized with aqueous NaOH solution (20%) to adjust the pH to9-10. The mixture is extracted with ethyl acetate (3×50 mL) after whichthe combined organic layers are washed with brine (500 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate is concentrated in vacuo toafford the crude product which is slurried in a mixture of DCM/MTBE (3mL/15 mL). The resulting solid is then collected by filtration to afford7-chloropyrazolo[1,5-a]pyrimidin-5-amine (Z-3).

Method N

General Method for Synthesis of2-amino-4-chloropyrimidine-5-carboxylate:

To a stirred solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1.6g, 7.24 mmol) in 1,4-dioxane (15 mL) at 0-5° C. under argon, ammoniumhydroxide (28-30%, 2.56 mL, 21.72 mmol) is added slowly and theresulting mixture is stirred from 0° C. to RT for 2 h. The reaction iscomplete based on TLC (30% EA/Hex, Rf=0.3 for ethyl2-amino-4-chloropyrimidine-5-carboxylate (Hinge-1); Rf=0.5 for ethyl4-amino-2-chloropyrimidine-5-carboxylate) and LC-MS analysis. Themixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine, dried over Na₂SO₄ and filtered. The filtrateis mixed with silica gel and then concentrated in vacuo. The residue isloaded to the top of silica gel packed in a glass column and eluted with0-100% ethyl acetate/hexanes to afford ethyl2-amino-4-chloropyrimidine-5-carboxylate (Hinge-1).

The other regio isomer, ethyl 4-amino-2-chloropyrimidine-5-carboxylate,is also isolated.

Method O

General Method for Synthesis of 5-chloroimidazo[1,2-c]pyrimidine:

The mixture of 2,4-dichloropyrimidine (A-1) (20 g, 134 mmol),3,3-diethoxypropan-1-amine (19.6 g, 147 mmol) and Et₃N (20.5 mL, 147mmol) in ethanol (250 mL) is stirred at RT for 24 h. The mixture isconcentrated in vacuo and the residue is purified by flash columnchromatography to afford the2-chloro-N-(2,2-diethoxyethyl)pyrimidin-4-amine (A-2).

A mixture of 2-chloro-N-(2,2-diethoxyethyl)pyrimidin-4-amine (A-2) (20g, 81.3 mmol) and H₂SO₄ (conc, 12 mL, 220 mmol) is stirred at 65-70° C.for 2 h. The reaction mixture is allowed to cool to RT, poured intoice-water (50 mL) and then basified with cold aqueous NaOH solution(10%) to adjust the pH to 1-3 while keeping inner temperature between0-20° C. The precipitate is collected by filtration and dried in vacuoto afford imidazo[1,2-f]pyrimidin-5-ol (A-3).

A mixture of imidazo[1,2-f]pyrimidin-5-ol (A-3) (4 g, 29.6 mmol) inphosphoroxychloride (50 mL, 530 mmol) is stirred at reflux overnight.The mixture is allowed to cool to RT and concentrated in vacuo to removethe phosphoroxychloride. The residue is poured into ice water (30 mL),and then neutralized with saturated aqueous NaHCO₃ solution to adjustthe pH to 6 while keeping the temperature below 5° C. The mixture isstirred at RT for 30 min and then extracted with ethyl acetate (20mL×3). The combined organic layer is washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by flash column chromatography on silica gel (1-5%ethyl acetate-petroleum ether) to afford5-chloroimidazo[1,2-f]pyrimidine (A-4).

Method P

General Method for Synthesis of 4-chloropyrido[3,4-d]pyrimidine:

The mixture of 3-aminoisonicotinic acid (B-1) (7 g, 50 mmol) and DMF(0.2 mL) in thionyl chloride (100 mL) is stirred at reflux for 2 h. Themixture is then concentrated in vacuo. The residue is dissolved in THF(30 mL) and the resulting solution (solution A) is used directly in thenext step.

To a stirred mixture of ammonium hydroxide (100 mL), the above solutionA (30 mL) is added dropwise while the reaction temperature is maintainedbetween 25° C. to 30° C. using an ice-water bath. The resulting mixtureis stirred at RT for 2 h and then water (100 mL) is added. The organiclayer is separated, washed with water (100 mL×2), dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo to afford the amide(B-2).

The mixture of compound B-2 (2 g, 14 mmol) in triethoxy methane (50 mL)is stirred at reflux overnight. The mixture is allowed to cool to RT andfiltered. The filter cake is washed with water, and dried in vacuo toafford compound (B-3).

To a stirred solution (B-3) (1 g, 6.7 mmol) and DMF (0.1 mL) in CH₃CN(20 mL) at RT, POCl₃ (10 mL) is added and the resulting mixture isstirred at reflux overnight. The mixture is allowed to cool to RT andconcentrated in vacuo. The residue is diluted with water (30 mL),neutralized with saturated aqueous NaHCO₃ solution below 10° C. toadjust the PH to 8-9 and then extracted with ethyl acetate (100 mL×4).The combined organic layer is washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo. The residue is purifiedby flash column chromatography on silica gel (16-50% ethyl acetate-petroether) to afford compound (B-4).

Method Q

General Method for Synthesis of 5-chloropyrazolo[1,5-a]pyrimidine:

To a stirred mixture of 1H-pyrazol-5-amine (4 g, 48 mmol, 1 eq) in1,4-dioxane (20 mL), ethyl propiolate (5.08 g. 52 mmol, 1.06 eq) isadded dropwise and the resulting mixture is stirred at reflux for 4 h.The mixture is cooled to RT and filtered. The filter cake is washed withwater, and dried in vacuo to afford compound (C-2).

The solution of (C-2) (1.35 g, 10 mmol) and DMF (0.1 mL) in POCl₃ (10mL) is stirred at reflux overnight. The mixture is allowed to cool to RTand concentrated in vacuo. The residue is diluted with water (30 mL),neutralized with saturated aqueous NaHCO₃ solution below 10° C. toadjust the PH to 8-9 and then extracted with ethyl acetate (30 mL×2).The combined organic layer is washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo. The residue is purifiedby flash column chromatography on silica gel (16-50% ethyl acetate-petroether) to afford compound (C-3).

(ii) General Method for the Synthesis of Amine Cores:

Method E

General Conditions for the Preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

To a stirred mixture of a given o-methylbenzoic acid (E-1) (1.5 mol, 1eq) and DMF (2 mL) in DCM (1275 mL) at RT, oxalyl chloride (1.65 mol,1.1 eq) is added over 5 min and the resulting mixture is stirred at RTfor 2 h. The mixture is then concentrated in vacuo. The residue isdissolved in DCM (150 mL) and the resulting solution (solution A) isused directly in the next step.

To a stirred mixture of aniline (1.58 mol, 1.05 eq) and triethylamine(3.15 mol, 2.1 eq) in DCM (1350 mL), the above solution A (150 mL) isadded dropwise while the reaction temperature is maintained between 25°C. to 40° C. by an ice-water bath. The resulting mixture is stirred atRT for 2 h and then water (1000 mL) is added. The organic layer isseparated, washed with water (2×1000 mL), dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo. The product issuspended in n-heptane (1000 mL) and stirred at RT for 30 min. Theprecipitate is collected by filtration, rinsed with heptanes (500 mL)and further dried in vacuo to afford the amide (E-2).

To a stirred mixture of amide (E-2) (173 mmol, 1 eq) in anhydrous THF(250 mL) at −30° C. under an argon atmosphere, a solution ofn-butyllithium in hexanes (432 mol, 2.5 eq) is added dropwise over 30min while keeping inner temperature between −30° C. and −10° C. Theresulting mixture is then stirred at −30° C. for 30 min.

To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (260 mmol, 1.5 eq) inanhydrous THF (250 mL) at −30° C. under an argon atmosphere, a solutionof isopropylmagnesium chloride in THF (286 mmol, 1.65 eq) is addeddropwise over 30 min while keeping inner temperature between −30° C. and−10° C. The resulting mixture is stirred at −30° C. for 30 min. Thissolution is then slowly added to above reaction mixture while keepingthe inner temperature between −30° C. and −10° C. The resulting mixtureis stirred at −15° C. for 1 h. The reaction mixture is quenched withwater (50 mL) and then acidified with conc. HCl at −10° C.-0° C. toadjust the pH to 1-3. The mixture is allowed to warm to RT andconcentrated in vacuo. The residue is dissolved in MeOH (480 mL), andthen conc. HCl (240 mL) is added quickly at RT. The resulting mixture isstirred at reflux for 1 h. The reaction mixture is concentrated in vacuoto reduce the volume to about 450 mL. The residue is extracted with a2:1 mixture of heptane and ethyl acetate (2×500 mL). The aqueous layeris basified with concentrated ammonium hydroxide to adjust the pH to9-10 while keeping the inner temperature between −10° C. and 0° C. Themixture is then extracted with DCM (3×300 mL), washed with brine, driedover MgSO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is dissolved in MeOH (1200 mL) at RT. To this solution,D-(−)-tartaric acid (21 g, 140 mmol, 0.8 eq) is added in one portion atRT. After stirring at RT for 30 min, white solid precipitates out andthe mixture is slurried at RT for 10 h. The solid is collected byfiltration and rinsed with MeOH (3×50 mL). The collected solid issuspended in water (500 mL) and then neutralized with concentratedammonium hydroxide solution at RT to adjust the pH to 9-10. The mixtureis extracted with DCM (3×200 mL). The combined organic layers are washedwith brine, dried over MgSO₄ and filtered. The filtrate is concentratedin vacuo to afford (S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones (E-3).

Method E′

General Conditions for the preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

In one embodiment, an amino compound (E-3′) may be prepared followingMethod E′, wherein the intermediate (E-1′) may be prepared followingprocedures known in the art or the procedure as described in Method E.In one embodiment, intermediate (E-2′) may be prepared from intermediate(E-1′) by contacting intermediate (E-1′) with a base (e.g., “BuLi)followed by (S)-benzyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate. In one embodiment,the amino compound (E-3′) may be prepared from intermediate (E-2′) bycyclizing intermediate (E-2′) in the presence of an acid. In oneembodiment, the acid is H₂SO₄. In another embodiment, the acid is HCl.In one embodiment, the amount of the acid is about 1 to 20 equivalentsrelative to the amount of the intermediate (E-2′). In one embodiment,the acid is about 5 equivalents of H₂SO₄. In one embodiment, thecyclization occurs at about room temperature to 65° C.

In one embodiment, the cyclization provides the amino compound (E-3′)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 20:1.In one embodiment, the cyclization provides the amino compound (E-3′)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 10:1.In one embodiment, the cyclization provides the amino compound (E-3′)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 4:1. Itis to be understood that the methods provided herein are also suitablefor the preparation of (R)-enantiomer of the amino compound (E-3′) when(R)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate is usedin place of (S)-benzyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate.

Method F

General Conditions for the Preparation of(S)-6-(1-aminoethyl)-3-chloro-5-phenylthieno[3,2-c]pyridin-4(5H)-ones:

To a solution of ethyl-3-aminocrotonate (F-1) (64.6 g, 0.5 mol, 1.0 eq)and pyridine (44.5 mL, 0.55 mol, 1.1 eq) in THF (600 mL) at −20° C.,2-chloroacetyl chloride (59.3 g, 0.53 mol, 1.05 eq) is added dropwisewithin 1 h. The resulting mixture is stirred from −20° C. to RT for anadditional 2 h and then it is poured into H₂O (1200 mL). The mixture isextracted with ethyl acetate (3×1200 mL). The combined organic layer iswashed with H₂O (2×500 mL) and brine (500 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate is concentrated in vacuo to reduce thevolume to about 200 mL. The residue is slurried in petroether (400 mL)at RT for 30 min. The solid is collected by filtration, rinsed withpetroether (200 mL), and dried in vacuo to afford the product, (E)-ethyl3-amino-2-(2-chloroacetyl)but-2-enoate (F-2).

To a suspension of (E)-ethyl 3-amino-2-(2-chloroacetyl)but-2-enoate(F-2) (58.6 g, 0.29 mol, 1.0 eq) in EtOH (500 mL) at RT, 30% NaSHsolution (190 g, 1.018 mol, 3.6 eq) is added dropwise over 30 min andthe resulting mixture is stirred at RT for 3 h. The mixture is pouredinto H₂O (1.5 L) and stirred for 30 min. The precipitate is collected byfiltration and rinsed with H₂O (3×100 mL). The collected solid isre-dissolved in ethyl acetate (500 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo to afford the product,ethyl 4-hydroxy-2-methylthiophene-3-carboxylate (F-3).

To a stirred solution of ethyl 4-hydroxy-2-methylthiophene-3-carboxylate(F-3) (20.0 g, 0.11 mol, 1.0 eq) in DMF (150 mL) at −20° C. under argon,phosphoryl chloride (49.4 g, 0.32 mol, 3.0 eq) is added dropwise whilekeeping the reaction temperature below 10° C. The resulting mixture isstirred at RT for 30 min and then at 80° C. for 1 h. The reactionmixture is cooled to RT and poured into ice-water (800 mL). Theresulting mixture is neutralized with NaOAc to adjust the pH to 7-8. Theprecipitate is collected by filtration, rinsed with H₂O (150 mL), anddried in vacuo. The product is purified by flash column chromatographyon silica gel (5% ethyl acetate-petroether) to afford the product, ethyl4-chloro-5-formyl-2-methylthiophene-3-carboxylate (F-4).

To a mixture of ethyl 4-chloro-5-formyl-2-methylthiophene-3-carboxylate(F-4) (9.72 g, 41.77 mmol, 1.0 eq) in DMF (150 mL), Oxone (77.1 g, 125.3mmol, 3.0 eq) is added in portions and the resulting mixture is stirredat RT overnight. The mixture is poured into H₂O (800 mL) and stirred for30 min. The precipitate is collected by filtration, rinsed with H₂O (100mL) and then slurried in H₂O (80 mL) for 30 min. The solid is collectedby filtration, rinsed with H₂O (3×60 mL) and petroether (3×60 mL), anddried in vacuo to afford the product,3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5).

To a stirred solution of3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5)(7.79 g, 31.3 mmol, 1.0 eq) in AcOH (150 mL) at RT, HgO (7.46 g, 34.4mmol, 1.1 eq) is added and the resulting mixture is stirred at refluxfor 1 h. The reaction mixture is cooled to 50-60° C. and then aqueousHCl (750 mL, 2.4 M, 1.8 mol) is added. The resulting mixture is stirredat reflux for an additional 1 h. The mixture is allowed to cool to RTand extracted with methyl tert-butyl ether (3×200 mL). The combinedorganic layers are washed with sat. NaHCO₃ solution (3×200 mL), H₂O (200mL) and brine H₂O (200 mL) sequentially. The organic layer is dried overanhydrous Na₂SO₄ and filtered. The filtrate is concentrated in vacuo andthe residue is purified by flash column chromatography on silica gel (2%ethyl acetate-petroether) to afford the product, ethyl4-chloro-2-methylthiophene-3-carboxylate (F-6).

To a mixture of ethyl 4-chloro-2-methylthiophene-3-carboxylate (F-6)(4.98 g, 24.3 mmol, 1.0 eq) in EtOH (50 mL) ar RT, aqueous NaOH solution(20%, 14.6 g, 73.0 mmol, 3.0 eq) is added and the resulting mixture isstirred at reflux for 1 h. The mixture is allowed to cool to RT andconcentrated in vacuo. The residue is poured into ice water (30 mL) andneutralized with concentrated HCl to adjust the pH to 1-2 while keepingthe temperature below 5° C. The precipitate is collected by filtration,rinsed with H₂O (80 mL) and dried in vacuo to afford the product,4-chloro-2-methylthiophene-3-carboxylic acid (F-7).

To a stirred mixture of 4-chloro-2-methylthiophene-3-carboxylic acid(F-7) (6.8 mmol, 1.0 eq) and DMF (three drops) in DCM (25 mL), oxalylchloride (20.4 mmol, 3.0 eq) is added at 0-5° C. over 5 min. Theresulting mixture is stirred from 0° C. to RT overnight. The mixture isconcentrated in vacuo. The residue is dissolved in DCM (20 mL) and theresulting solution (solution C) is used directly in the next step.

To a stirred mixture of a given (R₃-substituted)phenylamine (7.47 mmol,1.1 eq.) and pyridine

(20.4 mmol, 3.0 eq.) in DCM (10 mL) at 0-5° C., solution C is added andthe resulting mixture is stirred at RT for 2 h. The mixture is dilutedwith DCM (150 mL), washed with aqueous HCl (1 M, 3×50 mL), H₂O (2×50 mL)and brine (2×50 mL) sequentially. The organic layer is dried overanhydrous Na₂SO₄ and filtered. The filtrate is concentrated in vacuo toafford the amide (F-8).

To a mixture of amide (F-8) (2.0 mmol, 1.0 eq.) in THF (3.5 mL) at −60°C. under argon, n-butyllithium solution (2.5 M in hexanes, 2.8 mL, 7.0mmol, 3.5 eq.) is added slowly while keeping the temperature below −50°C. The resulting mixture is stirred below −50° C. for 30 min to formsolution D.

To a stirred mixture of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.6 mmol, 1.3 eq) inanhydrous THF (3.0 mL) at −60° C. under argon, a solution ofisopropylmagnesium chloride in THF (2.0 M, 1.33 mL, 2.66 mmol, 1.33 eq.)is added dropwise over 30 min while keeping inner temperature below −50°C. The resulting mixture is stirred below −50° C. for an additional 30min and then it is added slowly to solution D while keeping innertemperature at −50° C. The resulting mixture is stirred between −50° C.and −40° C. for 1 h and then at RT for an additional 1 h. The reactionmixture is quenched with water (5.0 mL) and acidified with aqueous HCl(5 N) at 0° C. to adjust the pH to 5-6. The mixture is concentrated invacuo. The residue is dissolved in MeOH (3.0 mL) and concentrated HCl(1.5 mL) is added. The resulting mixture is stirred at reflux for 1 hand then concentrated in vacuo to remove MeOH. The residue is suspendedin H₂O (5.0 mL) and extracted with a 1:1 mixture of heptane and ethylacetate (3×20 mL). The aqueous layer is basified with saturated aqueousNH₄OH to adjust the pH to 8-9 and extracted with DCM (3×20 mL). Thecombined organic layers are washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate is concentrated in vacuo and theresidue is purified by flash column chromatography on silica gel (10%MeOH-DCM) to afford the product (F-9).

Method G

General Conditions for the Preparation of6-(1-aminoethyl)-3-methyl-isothiazolo[4,5-c]pyridin-4(5H)-ones:

To a solution of methyl 3-aminocrotonate (G-1) (10.0 g. 86.9 mmol) inanhydrous THF (200 mL) at 0° C., a solution of phosphoryl chloride (12.0mL. 95.6 mmol) in anhydrous DMF (28 mL) is added dropwise (over 10 min).The resulting mixture is stirred at 0° C. for 1 h and then stirred at30° C. for 4 h. The mixture is allowed to stand overnight in arefrigerator. Chilled ether (800 mL) is then added to the reactionmixture until a semiclear/oil residue is formed. The yellow ether layeris decanted. The oil residue is then dissolved in DCM (500 mL) andwashed with NaHS aqueous solution (2.0 M). The organic layer is washedwith H₂O (4×500 mL), dried over Na₂SO₄ and filtered. The filtrate isconcentrated in vacuo to afford the product, methyl3-amino-2-thioformylbut-2-enoate (G-2).

To a solution of methyl 3-amino-2-thioformylbut-2-enoate (G-2) (5.34 g,33.5 mmol) in EtOH (250 mL), a solution of meta-chloroperoxybenzoic acid(70-75%, 12.4 g, 50.3 mmol) in EtOH (150 mL) is added and the resultingmixture is stirred at reflux for 3 h. The mixture is allowed to cool toRT, quenched with saturated aqueous NaOH solution and then extractedwith ethyl acetate (2×200 mL). The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo to afford the product, 3-methylisothiazole-4-carboxylate (G-3).

To a solution of 3-methylisothiazole-4-carboxylate (G-3) (4.73 g, 30.1mmol) in THF-MeOH-H₂O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is addedand the resulting mixture is stirred at 40° C. for 16 h. The mixture isallowed to cool to RT and then acidified with concentrated HCl to adjustthe pH to 2-3. The precipitate is collected by filtration, rinsed withwater and dried in vacuo to afford the product, 3ethylisothiazole-4-carboxylic acid (G-4).

To a solution of 3-methylisothiazole-4-carboxylic acid (G-4) (3.9 g,27.3 mmol) in anhydrous THF (150 mL) at −78° C. under argon, n-butyllithium solution (27.3 mL, 68.3 mmol) is added dropwise and theresulting mixture is stirred at −78° C. for 1 h. To this mixture, asolution of iodide (13.9 g, 54.6 mmol) in THF (50 mL) is added slowlyand the resulting mixture is stirred at RT for 1 h. The mixture isacidified with concentrated HCl to adjust the pH to 3-4, and thenextracted with ethyl acetate. The organic layer is washed with aqueousNa₂SO₃ solution. The aqueous layer is extracted with ethyl acetate. Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo to afford the product,5-iodo-3-methylisothiazole-4-carboxylic acid (G-5).

To a solution of 5-iodo-3-methylisothiazole-4-carboxylic acid (G-5)(4.45 g, 16.5 mmol) and DMF (3 drops) in anhydrous DCM (60 mL), oxalylchloride solution (2.0 M in DCM, 16.5 mL, 33.1 mmol) is added dropwiseand the resulting mixture is stirred at RT for 2 h. The reaction mixtureis concentrated in vacuo to afford the acyl chloride intermediate as anoil. The intermediate is dissolved in anhydrous THF (100 mL). To thismixture, a given amine R₂NH₂ (24.8 mmol) and N,N-diisopropylethylamine(4.09 mL, 24.8 mmol) are added dropwise. The resulting mixture isstirred at RT for 1 h. The reaction mixture is quenched with water andextracted with ethyl acetate. The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo to afford the amide (G-6).

To a solution of amide (G-6) (18.6 mmol) and tributyl(vinyl)tin (8.19mL, 27.9 mmol) in DMF (30 mL) under argon, Pd(PPh₃)₄ (1.07 g, 0.93 mmol)is added. The resulting mixture is stirred at 90° C. for 2 h. Themixture is allowed to cool to RT, quenched with water and extracted withethyl acetate (2×300 mL). The combined organic layers are washed withbrine, dried over Na₂SO₄ and filtered. The filtrate is concentrated invacuo and the residue is purified by flash column chromatography onsilica gel (0-25% ethyl acetate-hexanes) to afford the product (G-7).

To a solution of (G-7) in anhydrous DMF (70 mL) at RT, sodium hydride(60% in mineral oil, 1.52 g, 37.9 mmol) is added in portions and theresulting mixture is stirred at RT for 45 min. To this mixture, ethylchloroacetate (4.73 mL, 44.2 mmol) is added dropwise and the resultingmixture is stirred for 2 h. The reaction mixture is quenched with waterand extracted with ethyl acetate. The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo to afford the product (G-8). The product obtained is used inthe next step without purification.

To a solution of (G-8) (12.62 mmol) in 1,4-dioxane-H₂O (3:1, 100 mL) atRT, osmium tetraoxide (4% wt in H₇₀, 1.0 mL, 0.13 mmol) is added and theresulting mixture is stirred for 30 min. To this mixture, sodiumperiodate (5.40 g, 25.24 mmol) is added and the resulting mixture isstirred at RT for 3 h. The mixture is filtered through celite and thefiltrate is extracted with ethyl acetate (2×100 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo to afford the product aldehyde(G-9). The product obtained is used in the next step withoutpurification.

To a solution of (G-9) (12.68 mmol) in a mixture of EtOH and ethylacetate (3:1, 200 mL), cesium carbonate (4.55 g, 13.95 mmol) is addedand the resulting mixture is stirred at 50° C. for 2 h. The mixture isallowed to cool to RT and concentrated in vacuo. The residue ispartitioned between water and ethyl acetate. The organic layer is washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo and the residue is purified by flash column chromatography onsilica gel (0-40% ethyl acetate-hexanes) to afford the product (G-10).

To a solution of (G-10) (2.48 mmol) in anhydrous MeOH (15 mL), NaBH₄(936 mg, 24.75 mmol) is added in portions and the resulting mixture isstirred at RT for 16 h. The mixture is partitioned between water andethyl acetate. The organic layer is washed with brine, dried over Na₂SO₄and filtered. The filtrate is concentrated in vacuo to afford productalcohol (G-11).

To a solution of (G-11) (5.21 mmol) in anhydrous DCM (100 mL), 4 Åmolecular sieves (powder, 2.84 G), NMO (N-methylmorpholine-N-oxide)(1.22 g, 10.43 mmol) and TPAP (tetrapropylammonium perruthenate) (92 mg,0.26 mmol) are added sequentially. The resulting mixture is stirred atRT for 1 h and then filtered through a celite/silica gel pad. Thefiltrate is concentrated in vacuo to afford aldehyde (G-12).

To a solution of (G-12) (1.05 g, 3.90 mmol) in anhydrous THF (100 mL) at−78° C. under argon, methylmagnesium chloride solution (3.0M in THF,3.25 mL, 9.75 mmol) is added dropwise and the resulting mixture isstirred from −78° C. to RT for 2 h. The mixture is quenched with water(50 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo to afford product (G-13).

To a solution of (G-13) (0.48 mmol) in anhydrous THF (8 mL) at 0° C.under argon, triphenyl phosphine (230 mg, 0.88 mmol) is added and theresulting mixture is stirred for 5 min. To this mixture, diphenylphosphoryl azide (0.24 mL, 1.12 mmol) is added followed by slow additionof diisopropyl azodicarboxylate (0.17 mL, 0.88 mmol) over a 20 minperiod of time. The resulting mixture is stirred from 0° C. to RT for 2h. The mixture is then partitioned between ethyl acetate and water. Theorganic layer is washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate is concentrated in vacuo and the residue is purified by ISCO(silica gel cartridge, 0-50% ethyl acetate-hexanes) to afford theproduct azide (G-14).

A mixture of azide (G-14) (0.2489 mmol) and palladium (10% weight oncarbon, 23 mg, 20% of starting material by weight) in anhydrous MeOH (5mL) is degassed and flushed with hydrogen (three cycles). The reactionmixture is stirred under a hydrogen atmosphere at RT for 1 h. Themixture is filtered through celite and rinsed with ethyl acetate. Thefiltrate is then concentrated in vacuo to afford the amine (G-15).

Method H

General Conditions for the Preparation of7-(1-aminoethyl-6-phenyl-1,6-naphthyridin-5(6H)-ones:

To a mixture of ethyl 2-cyanoacetate (H-1) (45.2 g, 400 mmol) and agiven ketone R₁C(O)Me (800 mmol) in glacial acetic acid (50 mL),piperidine (2 mL, 20 mmol) is added and the resulting mixture stirred atreflux for 24 h. The reaction mixture is allowed to cool to RT, and thenconcentrated in vacuo. The residue is diluted with water (200 mL) andextracted with ethyl acetate (3×200 mL). The combined organic layers arewashed with brine (50 mL), dried over Na₂SO₄ and filtered. The filtrateis concentrated in vacuo and the residue is purified by flash columnchromatography on silica gel (0-2% ethyl acetate-petroether) to affordthe product (H-2).

To a solution of (H-2) (285 mol) in absolute EtOH (300 mL),N,N-dimethylformamide dimethyl acetal (37.3 g, 313 mmol) is addeddropwise and the resulting mixture is stirred at reflux for 6 h. Themixture is allowed to cool to RT, and concentrated in vacuo to affordthe product (H-3). This material is used in the next step withoutfurther purification.

Dienoate (H-3) (148 mmol) is dissolved in AcOH (120 mL) and the mixtureis stirred at 40° C. A solution of 45% HBr-AcOH (120 mL) is addeddropwise, and then the mixture is stirred at 55° C. for 2 h. The mixtureis allowed to cool to RT, poured into ice-water, neutralized with solidNa₂CO₃, and then extracted with ethyl acetate (3×150 mL). The combinedorganic layer is washed with brine (50 mL), dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue ispurified by flash column chromatography on silica gel (5-20% ethylacetate-petroether) to afford the product (H-4).

To a solution of 4-substituted ethyl 2-bromolnicotinate (H-4) (52 mmol)in 1,4-dioxane (15 mL), a solution of NaOH (8.0 g, 200 mmol) in H₂O (15mL) is added and the resulting mixture is stirred at reflux for 12 h.The mixture is allowed to cool to RT, diluted with H₂O, and washed withethyl acetate (3×30 mL). The aqueous layer is acidified withconcentrated hydrochloric acid to adjust the pH to 1, and then extractedwith ethyl acetate (3×50 mL). The combined organic layers are washedwith brine (25 mL), dried over Na₂SO₄ and filtered. The filtrate isconcentrated in vacuo to afford the product nicotinic acid (H-5).

Compound (H-5) is then converted to (H-16) in analogous fashion to(G-15) in Method G.

(iii) General Conditions for Attachment of W_(d) Substituents:

Method I

A mixture of compound (E-3) (1.0 mmol, 1.0 eq), Wd-Cl or Wd-OTs (1.50mmol, 1.5 eq) and triethylamine (3.0 mmol, 3.0 eq) in n-BuOH (5 mL) isstirred at reflux for 1-5 h. The reaction mixture is allowed to cool toRT and then concentrated in vacuo. The residue is purified by flashcolumn chromatography on silica gel (eluting with a mixture solvent ofMeOH and DCM) to afford the product (I-1). The reaction can occur underother conditions known in the art that are suitable for S_(N)Ardisplacement reaction. In one embodiment, the reaction solvent is NMP.

(iv) General Conditions for Substitution of W_(d):

Method J

Quinolinone (J-1) (0.11 mmol, 1.0 eq) is suspended in ammonium hydroxide(10-35% solution, 20 mL) in a sealed tube and the resulting mixture isstirred at 140° C. overnight. The mixture is allowed to cool to RT andthen extracted with DCM (3×15 mL). The combined organic layers arewashed with brine, dried over Na₂SO₄ and filtered. The filtrate isconcentrated in vacuo and the residue is purified by columnchromatography on silica gel (1-2% MeOH/DCM) to afford compound (J-2) asthe product.

Method K

To a stirred mixture of nitrobenzoic acid (K-1) (1.0 mol, 1.0 eq) andDMF (2.0 mL) in toluene (800 mL), thionyl chloride (292 mL, 1.0 mol, 4.0eq) is added dropwise (over 15 min) and the resulting mixture is stirredat reflux for 1.5 h. The mixture is allowed to cool to RT and thenconcentrated in vacuo. The residue is dissolved in DCM (100 mL) to formsolution A, which is used directly in the next step.

To a stirred mixture of a given amine R₂—NH₂ (102.4 g, 1.1 mol, 1.1 eq)and triethylamine (280 mL, 2.0 mol, 2.0 eq) in DCM (700 mL), solution Ais added dropwise while keeping the reaction temperature below 10° C.The resulting mixture is allowed to warm to RT and then stirred at RTovernight. The reaction mixture is diluted with ice-water (1.0 L) andstirred for 15 min. The precipitate is collected by filtration, rinsedwith isopropyl ether (3×100 mL) and petroleum ether (3×100 mL), and thendried in vacuo to afford product amide (K-2).

A mixture of nitro-benzamide (K-2) (20.0 mmol, 1.0 eq) and DMF (cat.) intoluene (60 mL) at RT, thionyl chloride (12 mL, 164 mmol, 8.2 eq) isadded dropwise (over 5 min) and the resulting mixture is stirred atreflux for 2 h. The mixture is allowed to cool to RT and thenconcentrated in vacuo. The residue is dissolved in DCM (10 mL) to formsolution B, which is used directly in the next step.

To a stirred mixture of N-(tert-butoxycarbonyl)-L-alanine (16.0 mmol,0.8 eq) and N,N-diisopropylethylamine (4.0 g, 31.0 mol, 1.5 eq) in DCM(20 mL), solution B is added dropwise while keeping the reactiontemperature between 0-10° C. The resulting mixture is stirred at thistemperature for 1 h and then stirred at RT overnight. The reactionmixture is quenched with ice-water (100 mL). The organic layer isseparated and the aqueous layer is extracted with DCM (2×80 mL). Thecombined organic layers are washed with brine, dried over Na₂SO₄ andfiltered. The filtrate is concentrated in vacuo and the residue isslurried in isopropyl ether (100 mL) for 15 min. The solid is collectedby filtration and dried in vacuo to afford product (K-3).

To a suspension of zinc dust (7.2 g, 110 mmol, 10.0 eq) in glacialacetic acid (40 mL) at 15° C., a solution of (K-3) (11.0 mmol, 1.0 eq)in glacial acetic acid (40 mL) is added and the resulting mixture isstirred at RT for 4 h. The mixture is poured into ice-water (200 mL) andneutralized with saturated aqueous NaHCO₃ solution to adjust the pH to8. The resulting mixture is extracted with DCM (3×150 mL). The combinedorganic layers are washed with brine, dried over Na₂SO₄ and filtered.The filtrate is concentrated in vacuo and the residue is purified byflash chromatography on silica gel (7% ethyl acetate-petroleum ether) toafford product (K-4).

Compound (K-4) (0.5 mmol, 1.0 eq) is dissolved in hydrochloric methanolsolution (2N, 20 mL) and the resulting mixture is stirred at RT for 2 h.The mixture is concentrated in vacuo. The residue is diluted with water(30 mL) and then neutralized with saturated aqueous NaHCO₃ to adjust thepH to 8 while keeping the temperature below 5° C. The resulting mixtureis extracted with DCM (3×30 mL). The combined organic layers are washedwith brine, dried over Na₂SO₄ and filtered. The filtrate is concentratedin vacuo and the residue is slurried in petroleum ether (10 mL). Thesolid is collected by filtration and dried in vacuo to afford product(K-5).

The quinazolinone (K-5) can be used to synthesize compounds describedherein using, for example, Method I to couple the amine to W_(d) groups.

Method L

To 2-chloro-6-methylbenzoic acid (L-1) (8.00 g, 46.9 mmol) in a dryround bottom flask under N₂ is added 50 mL of dry THF. The resultingmixture is cooled to −25° C. Then, n-hexyllithium (88 mL, 202 mmol) (2.3M in hexanes) is added, and the reaction is stirred at −20° C. for about20 min.

To compound (L-2) (14.16 g, 61.0 mmol) in a second dry round bottomflask under N₂ is added 70 mL of dry THF. The mixture is cooled to about−10° C. To the cold mixture is slowly added isopropyl magnesium chloride(63.3 ml, 2 M, 127 mmol). The resulting mixture is then stirred at −10°C. for about 20 min. Then, this mixture is slowly cannulated drop wiseinto the flask containing the (L-1) reaction while maintaining thetemperature at −20° C. After addition is complete, the reaction isslowly warmed to RT and stirred at RT for about 1.6 hours. The reactionmixture is then cooled to −10° C. and quickly cannulated to anotherflask containing 15 mL of ethyl acetate and 10 mL of isobutyric acid at−10° C. under N₂. After stirring for about 5 minutes, 10 mL of water israpidly added. The cooling bath is removed, and the reaction mixture isstirred for 10 minutes at RT. The mixture is transferred to a separationfunnel, and water (200 mL) is added. The water layer is extracted withEtOAc (3×400 mL). The aqueous layer is then acidified with HCl (2M) topH 3, and is extracted with EtOAc (3×500 mL), dried over sodium sulfateand concentrated in vacuo. The resulting material is purified by silicagel column chromatography using 0-10% MeOH in DCM to afford benzoic acid(L-3).

A mixture of benzoic acid (L-3) (5.00 g, 14.63 mmol) in acetic anhydride(10 mL) is stirred in a round bottom flask at 70° C. for about 2.5hours. Then, the remaining acetic anhydride is removed in vacuo. Theresidue is purified using silica gel column chromatography usingEtOAc/hexanes to afford lactone (L-4).

To a mixture of R, —NH, (197 mg, 1.54 mmol) in 2 mL of DCM is addedAlMe₃ (0.772 ml, 1.54 mmol). The mixture is stirred for about 15 min.Then, a solution of lactone (L-4) (100 mg, 0.309 mmol) in 2 mL of DCM isadded, and the reaction is stirred at RT for about 3 hours. The reactionmixture is then quenched with addition of 10 mL of Rochelle's salt andstirring for about 2 hours. The mixture is diluted with DCM, washed withbrine, dried with Na₂SO₄ and concentrated in vacuo to afford the amide(L-5) which is carried directly to the next reaction.

To the amide (L-5) in 5 mL of isopropanol is added 3 mL of concentratedHCl. The reaction is heated at 65° C. for about 3 hours. After coolingto RT, the mixture is concentrated in vacuo. The solid is suspended in15 mL of DCM, followed by the addition of 10 mL of sat. NaHCO₃. Thismixture is then stirred at RT for about 30 min, then 50 mL of DCM isadded. The layers are separated and the organic layer is dried withNa₂SO₄ and concentrated in vacuo to afford isoquinolinone (L-6).

Method L′:

General Conditions for the Preparation of(S)-3-(1-aminoethyl)-isoquinolin-1(2H)-ones:

In some embodiments, isoquinolinone (L-6) may be prepared by followingthe procedures exemplified in Method L′. In one embodiment, intermediate(L-2′) is prepared by contacting intermediate (L-2) with TFA followed byCF₃COOEt. In one embodiment, benzoic acid (L-3′) is prepared bycontacting o-methyl-benzoic acid (L-1) with a base (e.g., nHexLi),followed by intermediate (L-2′), and followed by purification by silicaplug or crystallization. In one embodiment, lactone (L-4′) is preparedby contacting benzoic acid (L-3′) with Ac₂O under conditions suitablefor cyclization. In one embodiment, amide (L-5′) is prepared bycontacting lactone (L-4′) with corresponding amine or aniline in thepresence of AlMe₃. In one embodiment, isoquinolinone (L-6) is preparedby contacting amide (L-5′) with an acid under conditions suitable forcyclization and deprotection. In one embodiment, the acid is HCl.

In one embodiment, the cyclization provides the amino compound (L-6)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 20:1.In one embodiment, the cyclization provides the amino compound (L-6)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 10:1.In one embodiment, the cyclization provides the amino compound (L-6)with a ratio of (S)-enantiomer to (R)-enantiomer of about 1:1 to 4:1. Itis to be understood that the methods provided herein are also suitablefor the preparation of (R)-enantiomer of the amino compound (L-6) when(R)-enantiomer of intermediate (L-2) is used in place of (S)-enantiomerof (L-2).

A compound provided herein may contain one or more chiral center.Conventional techniques for the preparation/isolation of individualenantiomers include synthesis from a suitable optically pure precursor,asymmetric synthesis from achiral starting materials, or resolution ofan enantiomeric mixture, for example, by chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation. Inone embodiment, the enantiopurity of a compound provided herein may beimproved by contacting the compound provided herein with a suitablesolvent or mixture thereof, followed by filtration. In one embodiment,the solvent is a mixture of water and dichloromethane. In anotherembodiment, the solvent is a mixture of dichloromethane and methanol.

Method M

In one embodiment, the N-methylpyridinone boronic ester (M-3) may beprepared following procedures exemplified in Method M. In oneembodiment, pyridyl boronic ester (M-2) may be prepared by contactingpyridyl boronic acid (M-1) with pinacol under conditions suitable forthe formation of boronic esters. In one embodiment, theN-methylpyridinone boronic ester (M-3) may be prepared by contactingpyridyl boronic ester (M-2) with MeI under conditions suitable forO-methyl-to-N-methyl shifting.

Example 1

Amine I-1 was prepared according to Method E and then coupled to (A-3)using Method I to provide compound I-2. ESI-MS m/z: 428.0 [M+H]⁺.

Example 2

Amine I-3 was prepared according to Method E and then coupled to (A-3)using Method I to provide compound I-4. ESI-MS m/z: 412.2 [M+H]⁺.

Example 3

Amine I-5 was prepared according to Method E and then coupled to (A-3)using Method I to provide compound I-6. ESI-MS m/z: 412.0 [M+H]⁺.

Example 4

Intermediate amide I-12 was prepared from 2-chloro-6-methylbenzoic acidI-7 according to the following procedures:

To a solution of 2-chloro-6-methylbenzoic acid I-7 (50 g, 294 mmol, 1.0eq) in conc. H₂SO₄ (500 mL) at 0° C., fuming HNO₃ (20.4 g, 324 mmol, 1.1eq) was added slowly. The resulting mixture was stirred at 0° C. for 5min and then stirred at RT for 2 h. The reaction mixture was poured intoice-water (800 mL) and extracted with ethyl acetate (3×500 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to afford the productas a mixture of two regio-isomers, 6-chloro-2-methyl-3-nitrobenzoic acidI-8 and 6-chloro-2-methyl-5-nitrobenzoic acid I-8′. The mixture was useddirectly in the next step.

To a stirred solution of above obtained regio-isomer mixture of6-chloro-2-methyl-3-nitrobenzoic acid 8 and6-chloro-2-methyl-5-nitrobenzoic acid I-8′ (61.8 g, 287 mmol, 1.0 eq)and DMF (catalytic amount) in DCM (500 mL) at RT, oxalyl chloride (49mL, 574 mmol, 2.0 eq) was added slowly (over 5 min). The resultingmixture was stirred at RT for 2 h and then concentrated in vacuo. Theresidue was dissolved in DCM (150 mL) to form solution A.

To a mixture of aniline (32 g, 344 mmol, 1.2 eq) and triethylamine (87.5g, 861 mmol, 3.0 eq) in DCM (400 mL) at RT, solution A was addeddropwise. The resulting mixture was stirred for 15 min and then quenchedwith water (500 mL). The organic layer was separated and the aqueouslayer was extracted with DCM (3×500 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to afford the product as a mixture of tworegio-isomers, 6-chloro-2-methyl-3-nitro-N-phenylbenzamide 1-9 and2-chloro-6-methyl-3-nitro-N-phenylbenzamide I-9′. The mixture was useddirectly in the next step.

To a stirred mixture of 6-chloro-2-methyl-3-nitro-N-phenylbenzamide 9and 2-chloro-6-methyl-3-nitro-N-phenylbenzamide I-9′ (33.6.8 g, 116mmol, 1.0 eq) in EtOH (400 mL), SnCl₂2.H₂O (105 g, 464 mmol, 4.0 eq) wasadded and the resulting mixture was stirred at reflux for 3 h. Thereaction mixture was allowed to cool and concentrated in vacuo. Theresidue was poured into water (500 mL) and the mixture was extractedwith ethyl acetate (5×500 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (2-20% ethyl acetate-petroleum ether) toafford the regio-isomer, 3-amino-6-chloro-2-methyl-N-phenylbenzamideI-10. The remaining mixture of3-amino-6-chloro-2-methyl-N-phenylbenzamide I-10 and5-amino-6-chloro-2-methyl-N-phenylbenzamide I-10′ was collectedseparately. Compound I-10′ was obtained by further column chromatographypurification.

To a stirred mixture of 3-amino-6-chloro-2-methyl-N-phenylbenzamide I-10(10.3 g, 39.6 mmol, 1.0 eq) in fluoroboric acid (42%, 72 mL) at 0° C., asolution of sodium nitrate (5.5 g, 79.2 mmol, 2.0 eq) in H₂O (10 mL) wasadded dropwise over 30 min while keeping the reaction temperaturebetween 0° C. and 5° C. The resulting mixture was stirred at RT for 16h. The precipitate was collected by filtration, rinsed with cold water(2×5 mL), and dried in vacuo to afford the product I-11. The product wasused directly in the next step.

The intermediate I-11 (12.8 g, 35.7 mmol) was heated to 120° C. and thetemperature was maintained between 120° C. and 130° C. for 1 h. Themixture was cooled to 50° C. and poured into ice-water (50 mL). Theresulting mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (2-20% ethylacetate-hexanes) to afford the product,6-chloro-3-fluoro-2-methyl-N-phenylbenzamide I-12.

Amine I-13 was prepared from amide I-12 according to Method E and wasthen coupled to A-3 using Method I to provide compound I-14. ESI-MS m/z:446.0 [M+H]⁺.

Example 5

Amine I-15 was prepared from amide I-10′ in analogous fashion tocompound I-13 in Example 4. Amine I-15 was then coupled to (A-3) usingMethod I to provide compound I-16. ESI-MS 446.0 [M+H]⁺.

Example 6

Amine I-17 was prepared according to Method E and was then coupled to(A-3) using Method I to provide compound I-18. ESI-MS m/z: 412.2 [M+H]⁺.

Example 7

Amine I-19 was prepared according to Method E and was then coupled to(A-3) using Method I to provide compound I-20. ESI-MS m/z: 446.0 [M+H]⁺.

Example 8

Compound I-2 was converted to compound I-21 according to the followinggeneral procedure:

Compound I-2 (0.2 mmol, 1.0 eq), boronic acid (0.41 mmol, 2.0 eq),Pd(OAc)₂ (0.04 mmol, 0.2 eq),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.12 mmol, 0.6eq) and Na₂CO₃ (0.6 mmol, 3.0 eq) were dissolved in1-methyl-2-pyrrolidinone (10 mL). The resulting mixture was degassed andback-filled with argon three times, and then stirred at 160° C. under anargon atmosphere for 1.5 h. The mixture was concentrated in vacuo andthe residue was purified by flash column chromatography on silica gel(1:30, MeOH-DCM) to afford the product I-21 as a solid; ESI-MS m/z:474.2 [M+H]⁺.

Example 9

Amine I-22 was prepared according to Method E and was then coupled to(A-3) using Method I to provide compound I-23. ESI-MS m/z: 392.2 [M+H]⁺.

Example 10

Compound I-24 was prepared from compound I-23 using the analogouscoupling procedures for the synthesis of compound I-21 in Example 8.ESI-MS m/z: 438.2 [M+H]⁺.

Example 11

Compound I-25 was prepared from compound I-20 using the analogouscoupling procedures for the synthesis of compound I-21 in Example 8.ESI-MS m/z: 492.2 [M+H]

Example 12

Amine I-26 was prepared according to Method G and was then coupled to(A-3) using Method I to provide compound I-27. ESI-MS m/z: 415.2 [M+H]⁺.

Example 13

Amine I-28 was prepared according to Method F and was then coupled to(A-3) using Method I to provide compound I-29. ESI-MS m/z: 434.0 [M+H]⁺.

Example 14

Compound I-30 was prepared from compound I-29 using the analogouscoupling procedures for the synthesis of compound I-21 in Example 8.ESI-MS m/z: 480.2 [M+H]⁺.

Example 15

Compound I-31 was prepared from I-7 in analogous fashion to E-2 inMethod E and was then converted to I-32 according to the followingprocedure:

To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamideI-31 (1.33 g, 5.0 mmol, 1.0 eq) and HMPA (0.87 mL, 5.0 mmol, 1.0 eq) inTHF (12.5 mL) at −60° C. under argon, n-butyllithium solution (2.5 M inhexanes, 5.0 mL, 12.5 mmol, 2.5 eq) was added dropwise while keeping thetemperature below −60° C. The resulting mixture was stirred between −70°C. and −60° C. for 30 min. To this mixture, (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.39 g, 6.0 mmol,1.2 eq) was added quickly. The resulting mixture was allowed to slowlywarm to RT (over 1 h) and then stirred at RT for an additional 2 h. Thereaction mixture was cooled to 0° C., quenched with water (5.0 mL), andthen acidified with aqueous HCl (5 M) to adjust the pH to 5-6. Themixture was concentrated in vacuo. The residue was suspended in amixture of MeOH (20 mL) and H₂O (5.0 mL), concentrated HCl (10.0 mL) wasadded and the resulting mixture was stirred at reflux for 2 h. Themixture was cooled to −5° C. and basified with saturated aqueous NH₄OHto adjust the pH to 8-9. The precipitate was filtered off and thefiltrate was extracted with DCM (3×20 mL). The combined organic layerswere dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by flash columnchromatography on silica gel (1-10% MeOH-DCM) to afford the product(S)-3-(1-aminoethyl)-8-chloro-2-(2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-oneI-32.

Compound I-32 was coupled to (A-3) using Method I to provide compoundI-33. ESI-MS m/z: 449.2 [M+H]⁺.

Example 16

Compound I-35 was prepared in two steps from compound I-1. Compound I-1was coupled to 1-methyl-1H-pyrazol-4-ylboronic acid pinacol ester usingthe procedure described in Example 8 to provide compound I-34. CompoundI-34 was then coupled to (B-2) using Method I to provide compound I-35.ESI-MS m/z: 508.2 [M+H]⁺.

Example 17

Compound I-36 was prepared from compound I-35 using Method J. ESI-MSm/z: 489.2 [M+H]⁺.

Example 18

Compound I-37 was prepared in analogous fashion to compound I-35 inExample 16 except that amine I-19 was used in place of amine I-1. ESI-MSm/z: 526.0 [M+H]⁺.

Example 19

Compound I-38 was prepared from compound I-37 using Method J. ESI-MSm/z: 507.2 [M+H]⁺.

Example 20

Compound I-39 was prepared in analogous fashion to compound I-35 inExample 16 except that amine I-22 was used in place of amine I-1. ESI-MSm/z: 472.2 [M+H]⁺.

Example 21

Compound I-40 was prepared from compound I-39 using Method J. ESI-MSm/z: 453.2 [M+H].

Example 22

Compound I-41 was prepared from compound I-2 according to the followingcoupling procedures:

Compound I-2 (230 umol), boronic acid (690 umol, 3 eq.), sodiumcarbonate (1.15 mmol, 5 eq.), RuPhos (70 mmol, 0.30 eq.), and palladiumdiacetate (35 umol, 0.15 eq.) were combined in a 2 mL microwave-reactiontube with a stir bar which was sealed with a septum. The atmosphere waspurged three times with vacuum, backfilling with dry argon, then1,4-dioxane (1.6 mL) and water (0.4 mL) were added. The reaction wassubjected to microwave heating at 125° C. for 3 h. The reaction mixturewas diluted with DCM (ca. 30 mL), treated with silica gel (ca. 1 g) andconcentrated; flash chromatography of this residue (on 15 g silica gel,eluting with a MeOH/DCM or EtOAc/hexanes gradient as required, approx.750 mL total eluent) gave the product I-41 as a light-yellow tooff-white powder. ESI-MS m/z: 485.8 [M+H]⁺.

The following compounds were also prepared from compound I-2 using theanalogous coupling conditions of Example 22:

Ex- ESI-MS ample Compound Boronic Acid m/z 23

  I-42

502.4  24

  I-43

486.2  25

  I-44

499.2  26

  I-45

501.1  27

  I-46

411.4  28

  I-47

487.2  29

  I-48

501.24

Example 30

Compound I-1 was coupled to (D-7) according to Method I to providecompound I-49. ESI-MS m/z: 427.2 [M+H]⁺.

Example 31

Compound I-19 was coupled to (D-7) using Method I to provide compoundI-50. ESI-MS m/z: 445.2 [M+H]⁺.

Example 32

Compound I-51 was prepared from compound I-49 using the analogouscoupling procedures for the synthesis of compound I-21 in Example 8.ESI-MS m/z: 473.2 [M+H]⁺.

Example 33

Compound 1 was coupled to (B-2) using Method I to provide compound 52.ESI-MS m/z: 462.07 [M+H]⁺.

Example 34

Compound I-1 was coupled to (C-5) using Method I to provide compoundI-53. ESI-MS m/z: 452.0 [M+H]⁺.

Example 35

Compound I-19 was coupled to (C-5) using Method I to provide compoundI-54. ESI-MS m/z: 470.0 [M+H]⁺.

Example 36

Compound I-55 was prepared from compound I-53 using the analogouscoupling procedures for the synthesis of compound I-21 in Example 8.ESI-MS m/z: 498.2 [M+H]⁺.

Example 37

Compound I-52 was converted to compound I-56 using Method J. CompoundI-57 was then coupled to 2-methoxypyrimidin-5-ylboronic acid using theanalogous procedure in Example 22 to provide compound I-57. ESI-MS m/z:517.25 [M+H]⁺.

Example 38

Compound I-58 was prepared in analogous fashion as compound I-57 inExample 37 except that 5-methoxypyridin-3-ylboronic acid was used inplace of 2-methoxypyrimidin-5-ylboronic acid. ESI-MS m/z: 516.25 [M+H]⁺.

Example 39

Compound I-59 was prepared in analogous fashion as compound I-57 inExample 37 except that 5-methylpyrimidin-5-ylboronic acid was used inplace of 2-methoxypyrimidin-5-ylboronic acid. ESI-MS m/z: 501.24 [M+H]⁺.

Example 40

Compound I-62 was prepared in 2 steps from compound I-60. Styrene I-60was prepared using the analogous coupling conditions in Example 22except that styrylboronic acid was used in place of2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.

Compound I-60 (0.98 mmol, 1 eq) was dissolved in THF (10 mL),tert-butanol (5 mL), and water (1.5 mL), and treated withN-methyl-morpholine N-oxide (700 mg, 6 eq) and a 4% aqueous solution ofosmium tetroxide (125 μL, 0.02 eq). The reaction was stirred at ambienttemperature overnight. The solvent was removed in vacuo and the residuewas taken up in water (50 mL), excess oxidant quenched with saturatedsodium sulfite solution (20 mL), and the product extracted three timeswith 40 mL of DCM. The combined organic phases were washed with brineand concentrated to a yellow solid.

This yellow solid was dissolved in THF (25 mL) and water (5 mL), thentreated with sodium periodate (1 g, 4.7 eq) and allowed to stir atambient temperature for 1 day. The reaction mixture was diluted withDCM, treated with silica gel (2 g) and concentrated in vacuo.Purification of the product by flash chromatography on silica gel,eluting with 40% to 80% EtOAc in hexanes, afforded the aldehyde I-61.

Aldehyde I-61 (0.96 mmol, 1 eq) in THF (13 mL) and tert-butanol (3 mL)was treated with isoprene (2 mL, 20 eq.), a 2.7M aqueous solution ofmonobasic sodium phosphate (2 mL, 5 eq), and a 1M aqueous solution ofsodium chlorite (3 mL, 3 eq). The reaction was stirred at ambienttemperature during 2 days, then treated with additional 1M chloritesolution (3 mL, 3 eq), and allowed to react overnight. The reactionmixture was added to water (90 mL) and DCM (60 mL) and acidified to pH 3by slow addition of 6M HCl (ca. 30 drops). The layers were separated andthe aqueous phase extracted twice with 40 mL DCM. The combined organicphases were washed with brine, dried on sodium sulfate, andconcentrated. Purification of the product by flash chromatography onsilica gel, eluting with 1-5% MeOH in DCM containing 1% acetic acid,afforded the acid I-62 as an off white solid. ESI-MS m/z: 436.17 [M+H]⁺.

Example 41

Compound I-63 was prepared from compound I-2 using the analogouscoupling procedures in Example 22 except that2-(tert-butoxycarbonylamino)pyrimidin-5-ylboronic acid was used in placeof 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.ESI-MS m/z: 487.23 [M+H]⁺.

Example 42

Amine I-64 was prepared according to Method H and was then coupled to(A-3) using Method I to provide compound I-65. ESI-MS m/z: 409.2 [M+H]⁺.

Example 43

Amine I-66 was prepared from (H-1) in analogous fashion to (H-16) inMethod H except that (4-methoxyphenyl)methanamine was used in place ofaniline in step 6 (amide formation). Amine I-66 was then coupled to(A-3) according to Method I to provide compound I-67. Compound I-67 wasconverted to I-68 according to the following procedure:

6-(4-Methoxybenzyl)-4-methyl-7-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)-1,6-naphthyridin-5(6H)-oneI-67 (60 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (4 mL) ina sealed tube and the resulting mixture was stirred at 140° C. for 48 h.The mixture was allowed to cool to RT, quenched with water and thenneutralized with saturated NaHCO₃ aqueous solution. The mixture wasextracted with ethyl acetate, washed with brine, dried with Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to afford the product,4-methyl-7-(1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)-1,6-naphthyridin-5(6H)-oneI-68. ESI-MS m/z: 333.2 [M+H]⁺.

Example 44

The following isoquinolinone compounds (L-6) were made in analogousfashion to Method L using the following R₂—NH₂ reagents.

TABLE 2 Compounds (L-6) ESI-MS m/z: R₂—NH₂ Compound (L-6) [M + H]⁺

299.10

335  

324.12

313.10

329.09

383.13

300.09

Example 45

Amine I-69 was prepared according to Method E. It was then coupled to(A-3) using Method I to provide compound I-70. ESI-MS m/z: 426.2 [M+H]⁺.

Example 46

To a stirred solution of compound I-52 (0.1 mmol, 1.0 eq) in THF (10 mL)at RT, sodium methoxide (0.2 mmol, 2 eq) was added and the resultingmixture was stirred at reflux for 1-2 h. The mixture was allowed to coolto RT and then extracted with DCM (15 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (1-2% MeOH/DCM) to afford compound I-71.ESI-MS m/z: 458.1 [M+H]⁺.

Example 47

Compound I-72 was prepared from compound I-71 in analogous fashion tocompound I-21 in Example 8. ESI-MS 532.2 [M+H]*.

Example 48

Compound I-73 was prepared in two steps from compound I-19. CompoundI-19 was coupled to2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineusing the procedure described in Example 8 to provide compound I-73a.Compound I-73a was then coupled to (A-3) using Method I to providecompound I-73. ESI-MS m/z: 520.1 [M+H]⁺.

Example 49

Compound I-74 was prepared from compound I-56 usingpyrimidin-5-ylboronic acid in the Suzuki reaction performed in analogousfashion to compound I-21 in Example 8. ESI-MS m/z: 487.2 [M+H]⁺.

Example 50

Compound I-75 was prepared from compound I-56 using(5-methylpyridin-3-yl)boronic acid in the Suzuki reaction performed inanalogous fashion to compound I-21 in Example 8. ESI-MS m/z: 500.3[M+H].

Example 51

Compound I-76 was prepared from compound I-2 using2-methylpyridin-4-ylboronic acid in the Suzuki reaction performed inanalogous fashion to compound I-21 in Example 8. ESI-MS m/z: 485.1[M+H]⁺.

Example 52

To a stirred solution of compound I-52 (0.1 mmol, 1.0 eq) in THF (10 mL)at RT, sodium benzyloxide (0.2 mmol, 2 eq) was added and the resultingmixture was stirred at reflux for 1-2 h. The mixture was allowed to coolto RT and then extracted with DCM (15 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (1-2% MeOH/DCM) to afford compound I-77a.ESI-MS m/z: 518.2 [M+H]

Example 53

Compound I-78 was prepared in two steps from compound I-73a. CompoundI-73a was coupled to (B-2) using Method I to provide compound I-78a.Compound I-78 was prepared from compound I-78a using Method J. ESI-MSm/z: 535.2 [M+H]⁺.

Example 54

Compound I-79 was prepared from compound I-1 in three steps. CompoundI-1 was coupled with 4-(tributylstannyl)pyridazine using the proceduredescribed in Example 8 to provide compound I-79a. Compound I-79a wasthen coupled to (B-2) using Method I to provide compound I-79b. CompoundI-79b was converted to compound I-79 using Method J. ESI-MS m/z: 487.2[M+H]⁺.

Example 55

Compound I-80 was prepared in three steps from compound I-19 inanalogous fashion to I-79 in Example 54. ESI-MS m/z: 505.2 [M+H]⁺.

Example 56

Compound I-81 was prepared from compound I-56 using2-methylpyridin-4-ylboronic acid in the Suzuki reaction performed inanalogous fashion to compound I-21 in Example 8. ESI-MS m/z: 500.3[M+H]⁺.

Example 57

Compound I-82 was prepared from compound I-56 using quinolin-3-ylboronicacid in the Suzuki reaction performed in analogous fashion to compoundI-21 in Example 8. ESI-MS m/z: 536.3 [M+H]⁺.

Example 58

Compound I-83 was prepared from compound I-56 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinein the Suzuki reaction performed in analogous fashion to compound I-21in Example 8. ESI-MS m/z: 525.3 [M+H]⁺.

Example 59

Compound I-84 was prepared in two steps from compound I-19 in analogousfashion to compound I-73a in Example 48. Compound I-84a was converted tocompound I-84b in analogous fashion to compound I-78 in Example 53.ESI-MS m/z: 519.2 [M+H]⁺.

Example 60

Compound I-85 was prepared in two steps from compound I-69. CompoundI-69 was coupled to (B-2) using Method I to provide compound I-85a.Compound I-85 was prepared from compound I-85a using Method J. ESI-MSm/z: 441.2 [M+H]⁺.

Example 61

Compound I-86a was prepared from 2-chloro-6-nitrobenzoic acid accordingto Method K. Compound I-86a was then coupled to (B-2) using Method I toprovide compound I-86b. Compound I-86b was converted to compound I-90using Method J. Compound I-90 was coupled to2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineusing the procedure described in Example 8 to provide compound I-86.ESI-MS m/z: 518.2 [M+H]⁺.

Example 62

Compound I-87 was prepared from I-90 by Suzuki coupling with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inanalogous fashion to compound I-86. ESI-MS m/z: 490.2 [M+H]⁺.

Example 63

Compound I-88 was prepared from I-90 by Suzuki coupling with2-methylpyridin-4-ylboronic acid in analogous fashion to compound I-86.ESI-MS m/z: 501.2 [M+H]⁺.

Example 64

Compound I-90 was coupled to 4-(tributylstannyl)pyridazine using theprocedure described in Example 8 to provide compound I-89. ESI-MS m/z:488.2 [M+H]⁺.

Example 65

To a solution of(S)-2-(1-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(30 mg, 0.067 mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (22mg, 0.1 mmol) in 1,4-dioxane-H₂O (4:1, 2 mL) in a sealed tube,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (15.6 mg, 0.034mmol), palladium(II) acetate (3.8 mg, 0.017 mmol), and Na₂CO₃ (21 mg,0.20 mmol) were added sequentially. The mixture was degassed andbackfilled with argon (three cycles), and then stirred at 120° C. for 1h. The mixture was allowed to cool to RT, and then partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 0-10% MeOH/DCM) to afford compound I-91,(S)-2-(1-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-5-(2-methylpyrimidin-5-yl)-3-phenylquinazolin-4(3H)-one(17 mg, 50% yield). ESI-MS m/z: 502.2 [M+H]⁺.

Example 66

Compound I-92 was prepared from compound I-52 using Method J. ESI-MSm/z: 443.1 [M+H].

Example 67

Compound I-93 was prepared in two steps from compound I-52. CompoundI-52 was converted to compound I-93a using 4-methoxybenzylamine inMethod J. Compound I-93a was coupled with2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineusing the procedure described in Example 8 to provide compound I-93.ESI-MS m/z: 637.4 [M+H]⁺.

Example 68

Compound I-56 (151 mg, 0.342 mmol), 2-Methyl-5-(tributylstannyl)thiazole(159 mg, 0.410 mmol), PdCl₂(amphos)₂ (24.19 mg, 0.034 mmol),PdCl₂(amphos)₂ (24.19 mg, 0.034 mmol) were charged in a dry vial. Thevial was evacuated and filled with Ar. Then degassed DMF (1 ml) wasadded and the mixture was stirred at 100° C. overnight. The reaction wascooled and the material was extracted with EtOAc and wash with waterthen brine. The organic layer was dried, filtered and concentrated todryness. Purification on silica gel (12 g) column and eluting withDCM/methanol (0 to 5% of methanol) provided compound I-94. ESI-MS m/z:506.2 [M+H]⁺.

Example 69

A mixture of compound I-52 (500 mg, 1.09 mmol, 1 equiv.),N,N-Diisopropylethylamine (0.56 mL, 3.28 mmol, 3 equiv.), 1.5 mLmethylamine (40% in water, 17.2 mmols, 15.8 equiv.) in 5 mL NMP washeated in a sealed tube at 120° C. for 45 h. 1.5 mL methylamine (40% inwater, 17.2 mmols, 15.8 equiv.) and 1 mL NMP were added and heated in asealed tube at 120° C. for another 18 h. The mixture was cooled, dilutedwith 10 mL 1:1 mixture of saturated brine and 2.5 M sodium carbonate and25 mL DCM. The aqueous layer was extracted with DCM (3×5 mL), thecombined organic layers were washed with water (10 mL), dried oversodium sulfate and the solvents were evaporated in vacuo. The residuewas chromatographed on silica gel (4 g, ISCO) using acetone-DCM aseluent. The product fractions were concentrated and the impurities werecrystallized off and the filtrates were concentrated under reducedpressure to provide 106 mg of compound I-95 as a light yellow solid.ESI-MS m/z: 452.2 [M+H]⁺.

Example 70

A mixture of compound I-52 (522 mg, 1.13 mmol, 1 equiv.),N,N-Diisopropylethylamine (0.58 mL, 3.39 mmol, 3 equiv.), 0.985 mLmethylamine (40% in water, 11.2 mmols, 10 equiv.) in 5 mL NMP was heatedin a sealed tube at 100° C. for 0.5 h. The clear solution was mixturewas cooled to room temp, diluted with 10 mL water, added to crushed ice,the precipitated white solids were filtered under suction, washed withwater (3×10 mL) and dried under high vacuum to give 516 mg compound I-96as a white solid. ESI-MS m/z: 457.2 [M+H]⁺.

Example 71

A mixture of compound I-96 (100 mg, 0.219 mmol, 1 equiv.),2-Methoxypyrimidine-5-boronic acid (67.4 mg, 0.438 mmol, 2 equiv.),sodium carbonate (116 mg, 1.094 mmol, 5 equiv.), and Pd-AMPHOS catalyst(31.0 mg, 0.044 mmol, 0.2 equiv.) in 2.9 mL degassed 4:1 dioxane-waterwas sparged with argon for 2 min. The mixture was sealed and heated at100° C. for 1 h, cooled, diluted with 10 mL each of DCM and water. Theorganic layer was collected, the aqueous layer was extracted with DCM(3×10 mL), the combined DCM layers were washed with water (10 mL), brine(10 mL), dried over sodium sulfate and the solvents were removed invacuo. The residue was purified on silica gel (12 g, ISCO) using 0-10%methanol in 1:1 DCM-EtOAc as eluent to provide 97 mg of compound I-97 asa light yellow solid. ESI-MS m/z: 531.3 [M+H]⁺.

Example 72

A mixture of compound I-96 (100 mg, 0.219 mmol, 1 equiv.),2-Methylpyrimidine-5-pinacol boronate (96 mg, 0.438 mmol, 2 equiv.),sodium carbonate (116 mg, 1.094 mmol, 5 equiv.), and Pd-AMPHOS catalyst(31.0 mg, 0.044 mmol, 0.2 equiv.) in 2.9 mL degassed 4:1 dioxane-waterwas sparged with argon for 2 min. The mixture was sealed and heated at100° C. for 1 h, cooled, diluted with 10 mL each of DCM and water. Theorganic layer was collected, the aqueous layer was extracted with DCM(3×10 mL), the combined DCM layers were washed with water (10 mL), brine(10 mL), dried over sodium sulfate and the solvents were removed invacuo. The residue was purified on silica gel (12 g, ISCO) using 0-10%methanol in 1:1 DCM-EtOAc to provide 110 mg of compound I-98 as a lightyellow solid. ESI-MS m/z: 515.3 [M+H]⁺.

Example 73

Compound I-99 was synthesized by coupling compound I-100 and2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineusing the procedure described in Example 8. ESI-MS m/z: 517.3 [M+H]⁺.

Example 74

Compound I-100 was prepared from compound I-1 coupled to (G-1) (seeBarlin, Gordon B.; Tan, Weng Lai, Australian Journal of Chemistry(1984), 37(12), 2469-77) using Method I. ESI-MS m/z: 443.2 [M+H]⁺.

Example 75

A mixture of compound I-56 (100 mg, 0.226 mmol, 1 equiv.),N,N-Diisopropylethylamine (0.16 mL, 0.9 mmol, 4 equiv.), 1.5 mLmethylamine (40% in water, excess) in 1 mL NMP was heated in a sealedtube at 120° C. for 18 h. Another 1.5 mL methylamine in water and 1 mLNMP were added, the tube was sealed and the mixture was heated at 120°C. for 52 h. The contents were cooled, added to 15 mL water, theprecipitate were filtered under suction, washed with water (3×10 mL) anddried under high vacuum to provide 71 mg of compound I-101 as a whitesolid. ESI-MS m/z: 438.3 [M+H]⁺.

Example 76

A mixture of compound I-56 (100 mg, 0.226 mmol, 1 equiv.),N,N-Diisopropylethylamine (0.16 mL, 0.9 mmol, 4.0 equiv.), 1.13 mLdimethylamine (2.0 M in THF, 10 equiv.) in 1 mL NMP was heated in asealed tube at 120° C. for 18 h. Another 2 mL dimethylamine in THF and 2mL NMP were added, the tube was sealed and the mixture was heated at120° C. for 52 h. The contents were cooled, diluted with EtOAc (20 mL),added to 30 mL water, the organic layer was collected, the aqueous layerwas extracted with EtOAc (3×10 mL), the combined organic layers werewashed with water (20 mL), brine (10 mL), dried over sod. sulfate andthe solvents were evaporated in vacuo. The residue was chromatographedon silica gel (4 g, ISCO) using DCM-Acetone to provide 38.8 mg ofcompound I-102 as a white solid. ESI-MS m/z: 452.3 [M+H].

Example 77

Amine I-103a (made by general method E) was coupled to (B-2) usingMethod I to provide compound I-103a. Compound I-103 was prepared fromcompound I-103a using Method J. ESI-MS m/z: 461.2 [M+H]⁺.

Example 78

Amine I-104 (prepared according to method L) was coupled to (A-3) usingMethod I to provide compound I-105. Compound I-105 was coupled to1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onein the Suzuki reaction performed in analogous fashion to compound I-21in Example 8 to provide compound 1406. ESI-MS m/z: 467.2 [M+H]⁺.

Example 79

Compound I-2 was coupled to1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onein the Suzuki reaction performed in analogous fashion to compound I-21in Example 8 to provide compound I-107. ESI-MS m/z: 501.2 [M+H]⁺.

Example 80

Amine II-1 was prepared using Method E and then coupled with (A-2) usingMethod G to provide compound II-2. ESI-MS m/z: 416.0 [M+H]⁺.

Example 81

Amine II-3 was prepared using Method E and was then coupled with (A-2)using Method G to provide compound II-4. ESI-MS m/z: 434.0 [M+H]⁺.

Example 82

Compound II-5 was prepared from compound II-2 according to the followingprocedure:

A mixture of(S)-8-chloro-2-phenyl-3-(1-(pyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)isoquinolin-1(2H)-oneII-2 (66 mg, 0.158 mmol, 1.0 eq),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66mg, 0.316 mmol, 2.0 eq), PdCl₂(dppf) (13 mg, 0.016 mmol, 0.1 eq) andNa₂CO₃ (84 mg, 0.79 mmol, 5.0 eq) was suspended in a mixture ofN,N-dimethylacetamide (5 mL) and water (2 mL). The resulting mixture wasdegassed and back-filled with argon three times and stirred at 80° C.under argon overnight. The mixture was concentrated in vacuo and theresidue was purified by flash column chromatography on silica gel (1-5%MeOH-DCM) to afford the product,(S)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenyl-3-(1-(pyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)isoquinolin-1(2H)-oneII-5 (43 mg, 60% yield). ESI-MS m/z: 462.2 [M+H]⁺.

Example 83

Amine II-6 was prepared using Method E and then coupled with (A-2) usingMethod G to provide compound II-7. ESI-MS m/z: 380.2 [M+H]⁺.

Example 84

Compound II-8 was prepared from compound II-7 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 426.2 [M+H]⁺.

Example 85

Compound II-9 was prepared from compound II-4 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 480.2 [M+H]⁺.

Example 86

Intermediate imidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate (B-6)was prepared according to Method B. Amine II-1 was then coupled to (B-6)using Method G to provide compound II-10. ESI-MS m/z: 416.2 [M+H]⁺.

Example 87

Amine II-6 was prepared using Method E and then coupled with (B-6) usingMethod G to provide compound II-11. ESI-MS m/z: 380.2 [M+H]⁺.

Example 88

Amine II-6 was prepared using Method E. Amine II-12 was coupled with(B-3) using Method G to provide compound II-13. ESI-MS m/z: 460.2[M+H]⁺.

Amine II-12 was prepared from II-6 according to the following procedure:

To a mixture of(S)-3-(1-aminoethyl)-8-chloro-2-cyclopropylisoquinolin-1(2H)-one II-6(878 mg, 3.35 mmol, 1.0 eq) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(815 mg, 3.92 mmol, 1.2 eq) in anhydrous DMA (10 mL) in a sealed tube,PdCl₂(dppf) (219 mg, 0.27 mmol, 0.08 eq) and aqueous Na₂CO₃ solution (1M, 10.0 mL, 10.0 mmol, 3.0 eq) were added and the resulting mixture wasstirred at 120° C. for 3 h. The reaction mixture was allowed to cool toRT, quenched with water, and then extracted with ethyl acetate (200mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO (silica gel cartridge, 0-8% MeOH-DCM) toafford the product,(S)-3-(1-aminoethyl)-2-cyclopropyl-8-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1(2H)-oneII-12 as a pink/magenta solid. ESI-MS m/z: 309.2 [M+H]⁺.

Example 89

Amine II-3 was prepared using Method E and then coupled with (B-6) usingMethod G to provide compound II-14. ESI-MS m/z: 434.0 [M+H]⁺.

Example 90

Compound II-16 was prepared from compound II-15 in analogous fashion tocompound II-13 in Example 88. ESI-MS m/z: 514.0 [M+H]⁺.

Example 91

Compound II-17 was prepared from compound II-14 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 480.2 [M+H]⁺.

Example 92

Compound II-18 was prepared from compound II-10 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 462.2 [M+H]⁺.

Example 93

Amine II-19 was prepared using Method F and then coupled with (A-2)using Method G to provide compound II-20. ESI-MS m/z: 422.0 [M+H]⁺.

Example 94

Compound II-21 was prepared from compound II-20 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 468.2 [M+H]⁺.

Example 95

Amine II-19 was coupled with (B-6) using Method G to provide compoundII-22. ESI-MS m/z: 422.0 [M+H]⁺.

Example 96

Compound II-23 was prepared from compound II-22 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 468.2 [M+H]⁺.

Example 97

Amine II-1 was coupled with (D-6) using Method G to provide compoundII-24. ESI-MS m/z: 417.0 [M+H]⁺.

Example 98

Compound II-28 was prepared in 4 steps according to the followingprocedures:

Compound II-26 was prepared from II-25 in analogous fashion to (E-2) inMethod E except that 2-(pyrrolidin-1-yl)ethanamine was used in place ofaniline and pyridine was used as a base in place of triethylamine.Compound II-26 was converted to II-27 according to the followingprocedure:

To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamideII-26 (1.33 g, 5.0 mmol, 1.0 eq) and HMPA (0.87 mL, 5.0 mmol, 1.0 eq) inTHF (12.5 mL) at −60° C. under argon, n-butyllithium solution (2.5 M inhexanes, 5.0 mL, 12.5 mmol, 2.5 eq) was added dropwise while keeping thetemperature below −60° C. The resulting mixture was stirred between −70°C. and −60° C. for 30 min. To this mixture, (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.39 g, 6.0 mmol,1.2 eq) was added quickly. The resulting mixture was allowed to slowlywarm to RT (over 1 h) and then stirred at RT for an additional 2 h. Thereaction mixture was cooled to 0° C., quenched with water (5.0 mL), andthen acidified with aqueous HCl (5 M) to adjust the pH to 5-6. Themixture was concentrated in vacuo. The residue was suspended in amixture of MeOH (20 mL) and H₂O (5.0 mL), concentrated HCl (10.0 mL) wasadded and the resulting mixture was stirred at reflux for 2 h. Themixture was cooled to −5° C. and basified with saturated aqueous NH₄OHto adjust the pH to 8-9. The precipitate was filtered off and thefiltrate was extracted with DCM (20 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by flash columnchromatography on silica gel (1-10% MeOH-DCM) to afford the product,(S)-3-(1-aminoethyl)-8-chloro-2-(2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-oneII-27)as a yellow solid.

Compound II-27 was then coupled with (A-2) using Method G to providecompound I-28. ESI-MS m/z: 437.2 [M+H]⁺.

Example 99

Amine II-27 was coupled with (B-6) using Method G to provide compoundII-29. ESI-MS m/z: 437.2 [M+H]⁺.

Example 100

Amine II-3 was coupled with (D-6) using Method G to provide compoundII-30. ESI-MS m/z: 435.0 [M+H]⁺.

Example 101

Amine II-3 was coupled with (C-4) using Method G to provide compoundII-31. ESI-MS m/z: 448.2 [M+H]⁺.

Example 102

Amine II-1 was coupled with (C-4) using Method G to provide compoundII-32. ESI-MS m/z: 430.2 [M+H]⁺.

Example 103

Compound II-33 was prepared from compound II-32 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 476.2 [M+H]⁺.

Example 104

Compound II-44 was prepared according to the following procedures:

Compound II-34 was prepared according to Method E. To a stirred mixtureof II-34 (10.0 mmol, 1.0 eq) in DCM (20 mL), saturated aqueous NaHCO₃solution (2.8 mL) was added. The mixture was cooled to 0° C. and9-fluorenylmethyl chloroformate (10.5 mmol, 1.05 eq) was added in oneportion. The resulting mixture was allowed to warm to RT and stirred atRT for 1 h. The organic layers were separated, washed with water (50mL×2), dried over anhydrous MgSO₄ and filtered. The filtrate wasconcentrated in vacuo to afford the product II-35.

Compound II-35 (10.0 mmol, 10.0 eq) was then dissolved in TFA (25 mL)and the resulting mixture was stirred at reflux for 1 h. The mixture wasallowed to cool to RT and concentrated in vacuo to remove TFA. Theresulting brown oil residue was partitioned between DCM (50 mL) andsaturated aqueous NaHCO₃ (50 mL) solution. The organic layer was washedwith water (20 mL×2), dried over anhydrous MgSO₄ and filtered. Thefiltrate was concentrated in vacuo to afford the product II-36.

A mixture of compound II-36 (45.0 mmol) and DMF (0.3 mL) in SOCl₂ (100mL) was stirred at reflux for 2 h. The mixture was allowed to cool to RTand concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel to afford the product II-37.

To a stirred mixture of II-37 (5.4 mmol, 1 eq), Pd(OAc)₂ (363 mg, 1.62mmol, 0.3 eq) and PPh₃ (846 mg, 3.24 mol, 0.6 eq) in THF (50 mL) at RT,tributyl(vinyl)tin (1.97 g, 5.94 mmol, 1.1 eq) was added and theresulting mixture was stirred at reflux overnight. The mixture wasallowed to cool to RT and filtered through silica gel (10 g). Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography on silica gel (1-5% MeOH-DCM) to afford theproduct II-38.

To a stirred mixture of II-38 (7.6 mmol, 1 eq) in a mixture of1,4-dioxane (40 mL) and H₂O (40 mL) at RT, osmium tetraoxide (5 mg) wasadded and the resulting mixture was stirred at RT for 30 min. To thismixture, sodium periodate (3.3 g, 15.2 mmol, 2 eq) was added and theresulting mixture was stirred at RT overnight. The reaction mixture wasfiltered through silica gel (10 g). The filtrate was extracted with DCM(3×60 mL), washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography on silica gel (1-5% MeOH-DCM) to afford thealdehyde II-39.

To a solution of compound II-39 (3.53 mmol, 1 eq) in DMF (40 mL) at RT,oxone (6.5 g, 10.59 mmol, 3 eq) was slowly added and the resultingmixture was stirred at RT overnight. The reaction mixture was pouredinto water (50 mL) and neutralized with concentrated ammonium hydroxideto adjust the pH value to 7-8. The mixture was stirred at RT for 30 minand then extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography on silica gel (1-5% MeOH-DCM) to afford thecarboxylic acid II-40.

To a solution of compound II-40 (0.327 mol, 1 eq) and DMF (0.1 mL) inDCM (10 mL), oxalyl chloride (83.1 mg, 0.654 mmol, 2 eq) was added andthe resulting mixture was stirred at RT for 1 h. The mixture wasconcentrated in vacuo to afford the acid chloride II-41 as a yellow oil.The product obtained was used directly in the next step withoutpurification.

To a solution of morpholine (34 mg, 0.392 mmol, 1.3 eq) andtriethylamine (100 mg, 0.981 mol, 3 eq) in DCM (20 mL), acid chlorideII-41 was added at RT. The resulting mixture was stirred at RT for 1.The reaction mixture was poured into water (50 mL) and extracted withDCM (3×50 mL). The combined organic layer was washed with brine, driedover Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by flash column chromatography on silica gel (1-5%MeOH-DCM) to afford the amide II-42.

To a stirred mixture of II-42 (1.76 mmol, 1 eq) in EtOH (50 mL) at RT,morpholine (3.05 g, 35.2 mmol, 20 eq) was added and the resultingmixture was stirred at reflux for 4 h. The mixture was allowed to coolto RT and then concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (1-10% MeOH-DCM) to afford the amineII-43.

Amine II-43 was then coupled with (D-6) using Method G to providecompound II-44. ESI-MS m/z: 438.2 [M+H].

Example 105

Compound II-45 was prepared from compound II-11 in analogous fashion tocompound II-5 in Example 82. ESI-MS m/z: 426.2 [M+H]⁺.

Example 106

Compound II-46 was prepared from compound II-1 in analogous fashion tocompound II-12 in Example 88 except that 2-methoxypyrimidin-5-ylboronicacid was used in place of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.Compound II-46 was then coupled to compound A-2 to provide compoundII-47 according to Method G. ESI-MS m/z: 490.2 [M+H]⁺.

Example 107

Compound II-46 was coupled with B-6 to provide compound II-48 accordingto Method G. ESI-MS m/z: 490.2 [M+H]⁺.

Example 108

Compound II-49 was prepared by coupling compound Z-3 to compound II-1according to Method G. ESI-MS m/z: 431.2 [M+H]⁺.

Example 109

Compound II-50 was prepared from compound II-49 in analogous fashion tocompound II-5 in Example 82 except that 2-methoxypyrimidin-5-ylboronicacid was used in place of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.ESI-MS m/z: 505.2 [M+H]⁺.

Example 110

Amine III-1 was prepared according to Method Q. Compound III-1 was thenconverted to compound III-2 using Method S. The THP protecting group wasthen removed according to the following general procedure:

To a mixture of compound III-2 in ethanol (4 vol)/water (2 vol),concentrated HCl solution (2 vol) was added and the resulting mixturewas stirred at RT for 1 h. The resulting mixture was diluted with coldwater, basified with saturated aqueous NaHCO₃ to adjust the pH to 8-9and then extracted with DCM (3×20 vol). The combined organic layers werewashed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo. The residue purified by flash columnchromatography on silica gel eluting with a mixture solvent of MeOH andDCM to afford compound III-3. ESI-MS m/z: 451.0[M+H]⁺.

Example 111

Compound III-4 was prepared by coupling amine III-1 and (B-3) accordingto Method Q. ESI-MS m/z: 462.0 [M+H]⁺.

Example 112

Compound III-5 was prepared by coupling amine III-1 and (1-4) accordingto Method S. ESI-MS m/z: 468.0 [M+H]⁺.

Example 113

Compound III-6 was prepared by coupling amine III-1 and (J-2) accordingto Method S. ESI-MS m/z: 450.2 [M H]

Example 114

Compound III-7 was prepared by coupling amine III-1 and (K-3) accordingto Method S. Compound 8 was then prepared according to the followingprocedure:

To a suspension of(S)-3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-oneIII-7 (50 mg, 0.104 mmol, 1.0 eq) in MeOH (20 mL), palladium on carbon(10%, 17 mg) and triethylamine (0.1 mL, 0.72 mmol, 6.9 eq) were added.The resulting mixture was degassed and back-filled with hydrogen (threecycles), and then stirred at RT under hydrogen overnight. The mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (5-10% ethylacetate-petroether) to afford the product,(S)-3-(1-(imidazo[1,2-b]pyridazin-8-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-oneIII-8. ESI-MS m/z: 450.2 [M+H]⁺.

Example 115

Amine III-9 was prepared according to Method Q. Compound III-10 was thenprepared by coupling compound III-9 with (1-4) using Method S. ESI-MSm/z: 486.0 [M+H]

Example 116

Compound III-11 was prepared by coupling amine III-9 and (J-2) accordingto Method S. ESI-MS m/z: 468.2 [M+H]⁺.

Example 117

Compound III-12 was prepared by coupling amine III-9 and (B-3) accordingto Method S. ESI-MS m/z: 480.2 [M+H]⁺.

Example 118

Compound III-13 was prepared in analogous fashion to compound III-3 inExample 75 except that amine III-9 was used in place of amine III-1.ESI-MS m/z: 469.0 [M+H]⁺.

Example 119

Compound III-14 was prepared by coupling amine III-9 and (K-3) accordingto Method S. ESI-MS m/z: 502.0 [M+H]⁺.

Example 120

Compound III-15 was prepared from compound III-14 using the analogousprocedure for compound III-8 in Example 79. ESI-MS m/z: 468.2 [M+H]⁺.

Example 121

Compound III-16 was prepared by coupling amine III-1 and (A-2) accordingto Method S. This compound III-16 was then converted to compound III-17according to the analogous procedure for compound III-3 in Example 75.ESI-MS m/z: 466.0 [M+H]⁺.

Example 122

Compound III-18 was prepared by coupling amine III-1 and (F-1) accordingto Method S. ESI-MS m/z: 468.2 [M+H]⁺.

Example 123

Compound III-19 was prepared by coupling amine III-1 and (E-5) accordingto Method S. ESI-MS m/z: 475.0 [M+H]⁺.

Example 124

Compound III-20 was prepared by coupling amine III-1 and (G-3) accordingto Method S. ESI-MS m/z: 493.2 [M+H]⁺.

Example 125

Compound III-21 was prepared by coupling amine III-1 and (L-6) accordingto Method S. ESI-MS m/z: 451.2 [M+H]⁺.

Example 126

Compound III-22 was prepared by coupling amine III-1 and (M-3) accordingto Method S. ESI-MS m/z: 496.2 [M+H]⁺.

Example 127

Compound III-23 was prepared from III-22 according to the followingprocedure:

Compound III-22 (0.11 mmol, 1.0 eq) was suspended in ammonium hydroxide(10-35% solution, 20 mL) in a sealed tube and the resulting mixture wasstirred at 140° C. overnight. The mixture was allowed to cool to RT andthen extracted with DCM (3×15 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (1-2% MeOH-DCM) to afford compound III-23.ESI-MS m/z: 477.2 [M+H]⁺.

Example 128

Compound III-24 was prepared by coupling amine III-1 and commerciallyavailable 5,7-dichlorothiazolo[5,4-d]pyrimidine according to Method S.ESI-MS m/z: 502.0 [M+H]⁺.

Example 129

Compound III-25 was prepared from compound III-24 in analogous fashionto compound III-23 in Example 92. ESI-MS m/z: 473.2 [M+H]⁺.

Example 130

Compound III-26 was prepared by coupling amine III-1 and (I-4) accordingto Method S. ESI-MS m/z: 482.0 [M+H]⁺.

Example 131

Compound III-27 was prepared by coupling amine III-1 and (C-6) accordingto Method S. ESI-MS m/z: 451.2 [M+H]⁺.

Example 132

Compound III-28 was prepared by coupling amine III-1 and (D-4) accordingto Method S. ESI-MS m/z: 451.2 [M+H]⁺.

Example 133

Compound III-29 was prepared by coupling amine III-1 and (N-5) accordingto Method S. ESI-MS m/z: 464.0 [M+H]⁺.

Example 134

Compound III-30 was prepared in analogous fashion to compound III-17 inExample 88 except that amine III-9 was used in place of amine III-1 asstarting material. ESI-MS m/z: 484.2 [M+H]⁺.

Example 135

Compound III-31 was prepared by coupling amine III-1 and (0-8) accordingto Method S except that N,N-diisopropylethylamine was used in place oftriethylamine. ESI-MS m/z: 461.2 [M+H]⁺.

Example 136

Compound III-32 was prepared by coupling amine III-1 and (H-2) accordingto Method S. ESI-MS m/z: 494.0 [M+H]⁺.

Example 137

Compound III-36 was prepared from amine III-1 according to the followingprocedures:

To a mixture of(S)-3-(1-aminoethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-oneIII-1 (1.0 g, 3.0 mmol, 1.0 eq) and 2,4-dichloro-3-nitropyridine (578mg, 3.0 mmol, 1.0 eq) in EtOH (10 mL), triethylamine (608 mg, 6.0 mmol,2.0 eq) was added and the resulting mixture was stirred at refluxovernight. The mixture was allowed to cool to RT and then concentratedin vacuo. The resultant residue was purified by flash columnchromatography on silica gel (1% MeOH-DCM) to afford the product,(S)-3-(1-(2-chloro-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-oneIII-33.

To a solution of(S)-3-(1-(2-chloro-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1 (2H)-one III-33 (500 mg, 1.0 mmol, 1 eq) in MeOH (10 mL),sodium hydrosulphide (69 g, 1.29 mmol, 1.2 eq) was added and theresulting mixture was stirred at reflux for 2 h. The mixture was allowedto cool to RT and then concentrated in vacuo. The residue was purifiedby flash column chromatography on silica gel (2-3% MeOH-DCM) to affordthe product, (S)-3-(1-(2-mercapto-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-34.

A mixture of(S)-3-(1-(2-mercapto-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-34 (120 mg, 0.247 mmol, 1.0 eq) andstannous chloride dihydrate (297 mg, 1.32 mmol, 5.3 eq) in EtOH (5 mL)was stirred at refluxed for 2 h. The resulting mixture was cooled to RTand concentrated in vacuo. The residue was suspended in water (5 mL),neutralized with saturated NaHCO₃ solution to adjust the pH to 7-8 andthen extracted with ethyl acetate (5 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to afford the product,(S)-3-(1-(3-amino-2-mercaptopyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-oneIII-35.

A mixture of(S)-3-(1-(3-amino-2-mercaptopyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-35 (80 mg, 0.175 mmol, 1.0 eq) intriethyl orthoformate (180 mL) was stirred at reflux for 2 h. Thereaction mixture was allowed to cool to RT and then concentrated invacuo. The residue was purified by flash column chromatography on silicagel (1-2% MeOH-DCM) to afford the product,(S)-2-phenyl-3-(1-(thiazolo[5,4-b]pyridin-7-ylamino)ethyl)-8-(trifluoromethyl)isoquinolin-1(2H)-oneIII-36. ESI-MS m/z: 467.0 [M+H]⁺.

Example 138

Compound III-37 was prepared by coupling amine III-1 and (P-4) accordingto Method S. ESI-MS m/z: 486.2 [M+H]⁺.

Example 139

Amine III-38 was prepared according to Method R. Compound III-39 wasthen prepared by coupling amine III-38 and (1-4) according to Method S.ESI-MS m/z: 474.0 [M+H]⁺.

Example 140

Compound III-40 was prepared from amine III-38 in analogous fashion tocompound III-3 in Example 75. ESI-MS m/z: 457.0 [M+H]⁺.

Example 141

Compound III-41 was prepared from amine III-38 and (B-3) according toMethod S. ESI-MS m/z: 468.0 [M H]⁺.

Example 142

Compound III-42 was prepared by coupling amine III-1 and commerciallyavailable 4-amino-6-chloropyrimidine-5-carbonitrile according to MethodS. ESI-MS m/z: 451.2 [M+H]⁺.

Example 143

Amine III-9 was prepared according to Method Q. Compound III-43a wasprepared from amine III-9 and M-3 according to Method S. CompoundIII-43a was converted to III-43 according to the following procedure:

To a stirred solution of quinolinone III-43a (0.1 mmol, 1.0 eq) in THF(10 mL) at RT, sodium methoxide (0.2 mmol, 2 eq) was added and theresulting mixture was stirred at reflux for 1-2 h. The mixture wasallowed to cool to RT and then extracted with DCM (15 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography on silica gel (1-2% MeOH/DCM) toafford compound III-43. ESI-MS m/z: 510.2 [M+H]⁺.

Example 144

Compound III-44 was prepared from amine III-1 and2-amino-4-chloropyrimidine-5-carbonitrile (Hinge-1) according to MethodS. ESI-MS m/z: 451.2 [M+H]⁺.

Example 145

Compound III-45 was prepared from amine III-9 and2-amino-4-chloropyrimidine-5-carbonitrile (Hinge-1) according to MethodS. ESI-MS m/z: 469.2 [M+H]⁺.

Example 146

Compound III-46 was prepared from amine III-9 and4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (H-2) according to MethodS. ESI-MS m/z: 512.0 [M+H]⁺.

Example 147

Compound III-43a was converted to compound III-47a in analogous fashionto compound III-43 in Example 143 except that sodium benzyloxide wasused in place of sodium methoxide. Compound III-47 was prepared fromIII-47a according to the following procedure:

To a solution of III-47a (280 mg, 0.478 mmol) in MeOH (30 mL) at RT,Pd/C (150 mg, 10%) was added and the resulting mixture was stirred underhydrogen overnight. The mixture was filtered and the filtrate wasconcentrated in vacuo to afford compound III-47. ESI-MS m/z: 496.1[M+H]⁺.

Example 148

Compound III-48 was prepared in five steps from 2,6-dichloro-9H-purineaccording to the following procedure: 2,6-dichloro-9H-purine (10 mmol,1.0 equiv) was dissolved in 30 mL N,N-dimethylformamide. Sodium hydride(11 mmol, 1.1 equiv) was added portion-wise at 0° C. and stirred for 10minutes, after which p-methoxylbenzyl chloride (11 mmol, 1.1 equiv) wasadded and the reaction was allowed to stir at room temperatureovernight. The reaction was then transferred to a separatory funnel withexcess ethyl acetate and water. The water layer was then extracted withethyl acetate (3×200 mL), dried over Na₂SO₄, and concentrated. Themixture was purified by silica gel chromatography, eluting with 10%ethyl acetate/diethyl ether, to provide III-48a.

III-48a was then coupled to compound III-9 using Method S to affordcompound III-48b. Compound III-48b was then converted to compoundIII-48c in analogous fashion to compound III-43 in Example 143 exceptthat sodium benzyloxide was used in place of sodium methoxide. CompoundIII-48c was then deprotected using analogous conditions as III-47 inExample 147 to provide III-48d. Compound III-48d was then furtherdeprotected to provide III-48 according the following procedure:Compound III-48d was dissolved in excess TFA and allowed to stir atreflux for 5 h, after which it was concentrated in vacuo. The residuewas resuspended in saturated NaHCO₃ and transferred to a separatoryfunnel where it was extracted with methylene chloride (2×200 mL). Theorganic layers were combined, concentrated and purified using flashsilica gel chromatography (7.5:1 methylene chloride/methanol) to provideIII-48. ESI-MS m/z: 485.2 [M+H]⁺.

Example 149

Compound III-49 was prepared from amine III-9 and4-amino-6-chloropyrimidine-5-carbonitrile according to Method S. ESI-MSm/z: 469.0 [M+H]⁺.

Example 150

4-Chloro-7-fluoroquinazoline was coupled with amine I-1 using Method Ito afford compound IV-1. ESI-MS m/z: 445.2 [M+H]⁺.

Example 151

Amine IV-2a was prepared using Method E. It was then coupled with2,4-dichloro-1,3,5-triazine using Method I to provide compound IV-2b.Compound IV-2b was converted to compound IV-2 according to the followingprocedure: Compound IV-2b (71 mg, 0.16 mmol) was suspended in ammoniumhydroxide (30 mL) in a sealed tube and the resulting mixture was stirredat 140° C. overnight. The mixture was allowed to cool to RT and thenextracted with DCM (15 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (1-2% MeOH/DCM) to afford compound IV-2 (20mg, 29% yield). ESI-MS m/z: 411.0 [M+H]⁺.

Example 152

4-Chloro-6,7-difluoroquinazoline was coupled with amine I-1 using MethodI to afford compound IV-3. ESI-MS m/z: 463.2 [M+H]⁺.

Example 153

Amine I-1 was prepared using Method E. It was then coupled with compound(A-4) using Method I to provide compound IV-4. ESI-MS m/z: 416.1 [M+H]⁺.

Example 154

Compound B-4 was coupled with amine I-1 using Method I to affordcompound IV-5. ESI-MS m/z: 428.2 [M+H]⁺.

Example 155

Compound C-3 was coupled with amine I-1 using Method I to affordcompound IV-6. ESI-MS m/z: 416.2 [M+H]⁺.

Example 156

Compound IV-7 was prepared from amine I-1 by coupling to2-chloro-7H-purine using Method I. ESI-MS m/z: 417.2 [M+H].

Example 157

Compound IV-8 was prepared from amine I-1 and commercially available2-aminonicotinaldehyde according to the following procedure: To astirred mixture of compound I-1 (150 mg, 0.5 mmol) and2-aminonicotinaldehyde (37 mg, 0.6 mmol) in MeOH (5 mL), acetic acid(0.2 mL) and NaBH₃CN (79 mg, 1.25 mmol) were added sequentially. Theresulting mixture was stirred at RT for 16 h and LC-MS showed about 60%conversion. Additional amounts of 2-aminonicotinaldehyde (18 mg, 0.3mmol) and NaBH₃CN (40 mg, 0.62 mmol) were added and the resultingmixture was stirred for 16 h. The reaction was quenched by aqueousNaHCO₃ solution, and then extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over Na₇SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by ISCO(12 g silica gel cartridge, 0-10% MeOH/DCM) to afford compound IV-8 (65mg, 32% yield). ESI-MS m/z: 405.0 [M+H]⁺.

Example 158

To a stirred solution of 6-chloropyridazin-3-amine (12.9 g, 0.1 mol) andtriethylamine (11.2 g, 0.11 mmol) in MeOH (20 mL), Pd/C (10%, 1.3 g) wasadded. The resulting mixture was degassed and back-filled with hydrogen(three cycles) and then stirred at RT under hydrogen atmosphere for 18h. The resulting mixture was filtered and the filtrate was concentratedin vacuo to afford pyridazin-3-amine, which was used in the next stepwithout further purification.

A mixture of pyridazin-3-amine (9.51 g, 0.1 mol) and 2-ethyl2-chloro-3-oxopropanoate (22.5 g, 0.15 mol) in EtOH (20 mL) was stirredat reflux overnight. The mixture was allowed to cool to RT andconcentrated in vacuo to remove EtOH. The residue was partitionedbetween water (100 mL) and ethyl acetate (100 mL). The organic layer wasseparated. The aqueous layer was extracted with ethyl acetate (2×50 mL).The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo. The residue wasslurried in isopropyl ether (50 mL) with stirring for 30 min, collectedby filtration and dried in vacuo to afford ethylimidazo[1,2-b]pyridazine-3-carboxylate (7.8 g, 40.8% yield).

To a solution of ethyl imidazo[1,2-b]pyridazine-3-carboxylate (1.91 g,10 mmol) in anhydrous THF (20 mL), lithium aluminium hydride (1.34 g, 35mmol) was added in portions over 15 min. After stirring at RT for 16 h,the mixture was quenched with ice-water (20 mL) and then extracted withethyl acetate (30 mL×2). The combined organic layers were washed withbrine, dried over Na₂SO₄ then filtered. The filtrate was concentrated invacuo to afford imidazo[1,2-b]pyridazin-3-ylmethanol (0.85 g, 57%yield).

A mixture of imidazo[1,2-b]pyridazin-3-ylmethanol (45 mg, 0.3 mmol) andDess-Martin periodinane (130 mg, 0.3 mmol) in anhydrous DCM (5 mL) werestirred at RT overnight. The reaction mixture was quenched with water (5mL). The organic layer was separated, dried over MgSO₄ and filtered. Thefiltrate was concentrated in vacuo to affordimidazo[1,2-b]pyridazine-3-carbaldehyde (40 mg, 90.7% yield).

To a stirred mixture of compound I-1 (60 mg, 0.2 mmol) andimidazo[1,2-b]pyridazine-3-carbaldehyde (30 mg, 0.2 mmol) in DCM (5 mL),acetic acid (24 mg, 0.4 mmol) and triacetoxyborohydride (85 mg, 0.42mmol) were added respectively. After stirring at RT for 2 h, the mixturewas quenched with water (10 mL). The organic layer was separated, driedover MgSO₄ and filtered. The filtrate was concentrated in vacuo toafford(S)-8-chloro-3-(1-(imidazo[1,2-b]pyridazin-3-ylmethylamino)ethyl)-2-phenylisoquinolin-1(2H)-one(IV-9) (75 mg, 87.2% yield). ESI-MS m/z: 430.2 [M+H]⁺.

Example 159

Compound IV-10a was coupled with2-chloro-5-(trifluoromethyl)pyrimidin-4-amine using Method I to affordcompound IV-10. ESI-MS m/z: 481.2 [M+H]⁺.

Example 160

To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.99 g, 26.0mmol, 1.0 eq) in dry DCM (150 mL) under argon, N-bromosuccinimide (6.02g, 33.8 mmol, 1.3 eq) was added and the resulting mixture was stirred atRT for 3 h. The reaction mixture was diluted with MeOH (30 mL) and thenconcentrated in vacuo to yield a slight brown solid. The residue wastriturated with H₂O (150 mL). The solid was collected by filtration andthen re-crystallized in MeOH to afford5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 66% yield).

To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.33 g,10.0 mmol, 1.0 eq) in anhydrous THF (100 mL) at −78° C. under argon,n-BuLi solution (2.5 M in THF, 8.8 mL, 22.0 mmol, 2.2 eq) was addeddropwise (over 10 min). The resulting mixture was stirred at −78° C. for1 h and then DMF (2.0 g, 11.0 mmol, 1.1 eq) was added dropwise (over 10min). The mixture was stirred at −78° C. for an additional 30 min andthen stirred at RT overnight. The reaction mixture was quenched with H₂O(50 mL) and then concentrated in vacuo. The residue was triturated withsaturated aqueous NH₄Cl solution. The solid was collected by filtration,rinsed with ethyl acetate, and dried in vacuo to afford4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.17 g, 65% yield).

To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde(1.17 g, 6.47 mmol, 1.0 eq) and hydroxylamine hydrochloride (0.54 g,7.77 mmol, 1.2 eq) in EtOH (25 mL), aqueous NaOH solution (0.31 g, 7.77mmol, 1.2 eq) in H₂O (4 mL) was added dropwise. The resulting mixturewas stirred at RT for 30 min and then was diluted with a sufficientamount of EtOH to allow stirring for additional 30 min. The solid wascollected by filtration, rinsed with H₂O and dried in vacuo to afford4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (0.89 g, 70%yield) as a mixture of isomers. ESI-MS m/z: 194.8 [M−H]⁻.

To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehydeoxime (865 mg, 4.40 mmol, 1.0 eq) in DCM (20 mL), thionyl chloride (3.1mL, 43.7 mmol, 10.0 eq) was added and the resulting mixture was stirredat RT overnight. The reaction mixture was concentrated in vacuo. Theresidue was suspended in water (60 mL) and saturated aqueous NaHCO₃ wasadded to adjust the pH to 4. The solid was collected by filtration,rinsed with water followed by ethyl acetate to afford the first batch ofproduct. The filtrate was then extracted with ethyl acetate (50 mL×3).The combined organic layer was washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo and the residue wascombined with the above-obtained solid. The crude product was thenre-crystallized in ethyl acetate/hexanes (1:1) and dried in vacuo toafford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (763 mg, 97%yield). ESI-MS m/z: 178.8 [M+H]⁺, 176.8 [M−H]⁻.

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile was coupled withamine I-1 using Method I to afford compound IV-11. ESI-MS m/z: 4420.2[M−H]⁻.

Example 161

To a stirred solution of trichloroacetonitrile (28.8 g, 200 mmol, 1 eq)in anhydrous THF (70 mL) at −60° C. under an argon atmosphere,2,2-dimethoxyethanamine (21.8 mL, 200 mmol, 1.0 eq) was added dropwiseover 5 min. The resulting mixture was allowed to warm to RT and stirredat RT for 4 h. The mixture was concentrated in vacuo and the residue wasadded in portions to a stirred solution of trifluoroacetic acid (100 mL)at −30° C. under argon. The resulting mixture was then stirred from −30°C. to RT overnight. The reaction mixture was concentrated in vacuo toafford 2-(trichloromethyl)-1H-imidazole. The crude product was used inthe next step without further purification.

The above-obtained residue was dissolved in EtOH (300 mL). To thissolution, conc. H₂SO₄ (98%, 30 mL, 522 mmol, 2.76 eq) was added dropwisewhile keeping the reaction temperature below 25° C. The resultingmixture was stirred at reflux for 7 h and then stirred at RT overnight.The mixture was concentrated in vacuo to remove EtOH. The resultingsuspension was diluted with ice-water (200 mL) and neutralized withconcentrated ammonium hydroxide to adjust the pH to 5-6 while keepingthe temperature below 5° C. The solid was collected by filtration,rinsed with water (10 mL×3), and dried in vacuo to afford the firstbatch of crude product (10 g). The filtrate was extracted with ethylacetate (200 mL×2). The combined organic layer was washed with brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The resulting residue was combined with the first batch crude productand then re-crystallized in isopropyl ether to afford ethyl1H-imidazole-2-carboxylate (18 g, 64.3% yield).

To a stirred solution of hydroxylamine-o-sulfonic acid (26.64 g, 235.8mmol, 3.0 eq) in H₂O (17 mL) at 0° C., ethyl 1H-imidazole-2-carboxylate(11.0 g, 78.6 mmol, 1.0 eq) was added and the resulting mixture wasstirred at 90° C. for 30 min. The mixture was cooled to RT and K₂CO₃(3.6 g, 26.2 mmol, 1.0 eq) was added in portions. The resulting mixturewas stirred at RT overnight, filtered and rinsed with H₂O (10 mL×3). Thefiltrate was extracted with ethyl acetate (50 mL×5). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was evaporated in vacuo and the residue was purified by flashcolumn chromatography on silica gel (1% MeOH in DCM) to afford ethyl1-amino-1H-imidazole-2-carboxylate (800 mg, 6.5% yield). ESI-MS m/z:156.1 [M+H]⁺.

A mixture of ethyl 1-amino-1H-imidazole-2-carboxylate (800 mg, 5.16mmol, 1.0 eq) and formamidine acetate (2.68 g, 25.78 mmol, 5.0 eq) inEtOH (100 mL) was stirred at reflux overnight. The resulting mixture wascooled to RT. The solid was collected by filtration, rinsed with EtOH(3×2 mL) and petroleum ether (2 mL×3), and then dried in vacuo to affordimidazo[1,2-f][1,2,4]triazin-4-ol (400 mg, 50.2% yield).

Imidazo[1,2-f][1,2,4]triazin-4-ol (400 mg, 2.94 mmol, 1.0 eq) wasdissolved in POCl₃ (10 mL, 109.2 mmol, 37.1 eq) and the resultingmixture was stirred at reflux for 2 h. The mixture was concentrated invacuo to remove POCl₃. The residue was poured into ice water (30 mL) andneutralized with saturated aqueous NaHCO₃ solution to adjust the pH to6-7 while keeping the temperature below 5° C. The mixture was extractedwith ethyl acetate (30 mL×4). The combined organic layer was washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by flash column chromatography onsilica gel (16% ethyl acetate in petro ether) to afford4-chloroimidazo[1,2-f][1,2,4]triazine (300 mg, 66.0% yield).

4-Chloroimidazo[1,2-f][1,2,4]-triazine was coupled with amine I-1 usingMethod I to afford compound IV-12. ESI-MS m/z: 417.2 [M+H]⁺.

Example 162

4-Chloroimidazo[1,2-f][1,2,4]triazine was coupled with amine I-19 usingMethod I to afford compound IV-13. ESI-MS m/z: 435.0 [M+H]⁺.

Example 163

4-Chloroimidazo[5,1-f][1,2,4]triazine was coupled with amine I-19 usingMethod I to afford compound IV-14. ESI-MS m/z: 435.0 [M+H]⁺.

Example 164

Compound IV-19 was isolated as a byproduct of the coupling reaction toprovide compound IV-20. ESI-MS m/z: 499.12 [M+H]⁺.

Example 165

Amine I-1 (300 mg, 1.0 equiv) was dissolved in dioxane (5 mL).2,4-Dichloropteridine (1.5 equiv) and diisopropylethyl amine weredissolved in 5 mL dioxance and added slowly to amine I-1. The reactionwas heated to 60° C. for 72 h after which point there was no startingmaterial by LC/MS analysis. The reaction was transferred to a separatoryfunnel with excess dichloromethane. The organic layer was washed withsaturated sodium bicarbonate (2×), brine (1×) and water (1×), dried oversodium sulfate and concentrated to provide crude material which waspurified using flash silica gel chromatography (gradient of 50-100%ethyl acetate/hexanes) to provide compound IV-20. ESI-MS m/z: 463.13[M+H]⁺.

Example 166

A 35 mL heavy-walled tube with PTFE stopper and PTFE-jacketed-siliconeo-ring seal was charged with isoquinolinone IV-23 (0.23 mmol) and1,4-dioxane (10 mL). The suspension was treated with ammonium hydroxidesolution (10 mL), and the tube sealed tightly and placed in a 110° C.bath overnight. After cooling, LC/MS showed a mixture of products and<10% remaining starting material. The reaction mixture was diluted with2 volumes of brine after which a solid is formed that was collected viavacuum filtration to provide amide IV-21. ESI-MS m/z: 453.17 [M+H]⁺.

Example 167

A 35 mL heavy-walled tube with PTFE stopper and PTFE-jacketed-siliconeo-ring seal was charged with isoquinolinone IV-20 (243 mg, 0.52 mmol)and 1,4-dioxane (10 mL). The suspension was treated with ammoniumhydroxide solution (10 mL), and the tube sealed tightly and placed in a140° C. bath overnight. After cooling, LC/MS showed complete conversionand the reaction mixture was transferred to a larger flask using 1-2 mLsof MeOH, then diluted with 2 volumes of brine. After stirring about 1 h,the resulting precipitate was collected by filtration, washing withwater. The product cake was dried in vacuo to give compound IV-22 as atan powder. ESI-MS m/z: 444.20 [M+H]⁺.

Example 168

Compound I-1 was reacted with 4,6-dichloronicotinonitrile according toMethod 1 to provide compound IV-23. ESI-MS m/z: 435.11 [M+H]⁺.

Example 169

A 35 mL heavy-walled tube with PTFE stopper and PTFE-jacketed-siliconeo-ring seal was charged with isoquinolinone IV-21 (0.14 mmol) and1,4-dioxane (4 mL). The suspension was treated with ammonium hydroxidesolution (30%, 5 mL), and the tube sealed tightly and placed in a 150°C. bath for 3 d. The mixture was then recharged with 5 mL of ammoniumhydroxide (30%, 5 mL) and heated for 24 additional hours at 170° C. Thereaction mixture transferred to a separatory funnel with excessmethylene chloride. The organic layer was washed with brine (1×) andwater (1×), dried over Na₂SO₄ and concentrated to provide material whichis 85% of compound IV-24 and 15% of starting material which was useddirectly for biochemical profiling. ESI-MS m/z: 434.18 [M+H]⁺.

Example 170

Compound IV-25a was prepared from compound I-1 by coupling to ethyl4-amino-2-chloropyrimidine-5-carboxylate using Method I. Compound IV-25awas then converted to compound IV-25 according to the followingprocedure: The mixture of compound IV-25a (300 mg, 0.65 mmol) and2-methoxypyridin-4-yl)boronic acid (149 mg, 0.98 mmol) in1,4-dioxane:water (3:1, 12 mL) was degassed and backfilled with argon(three cycles). To this mixture,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (121 mg, 0.26 mmol),palladium(II) acetate (29 mg, 0.13 mmol), and Na₂CO₃ (207 mg, 1.95 mmol)were added sequentially. The resulting mixture was degassed andbackfilled with argon (three cycles), and then stirred at 120° C. for 3h. The mixture was allowed to cool to RT, and then partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by ISCO column chromatography (silica gelcartridge, 0-10% MeOH/DCM) to afford compound IV-25 (160 mg, 46% yield).ESI-MS m/z: 537.2 [M+H]⁺.

Example 171

Compound I-1 was reacted with 2,4-dichloro-5-nitropyrimidine accordingto Method I to provide compound IV-26a. Compound IV-26a was thenconverted to compound IV-26 in 3 steps according to the followingprocedures: Compound IV-26a (450 mg, 1.0 equiv) was dissolved in 30 mLof methanol and purged with N₂. Palladium on carbon (1.0 equiv) wasadded and the reaction was flushed with H₂. The reaction was kept underan atmosphere of H₂ using a balloon and stirred at room temperature for12 h after which it was filtered through celite and washed with excessmethanol. The solution was concentrated to provide amine IV-26b whichwas used directly in the next step. Compound IV-26b (68 mg, 1.0 equiv)was dissolved in tetrahydrofuran (5 mL). Triphosgene was added (1.2equiv), followed by triethylamine (3.0 equiv) and the reaction washeated to 50° C. for 16 h. The reaction was cooled and transferred to aseparatory funnel with excess ethyl acetate. The organic layer waswashed with brine (1×), dried over Na₂SO₄ and concentrated under vacuumto provide crude material that was purified using CombiFlash silica gelchromatography (60% ethyl acetate/hexanes) to provide compound IV-26c.Compound IV-26c was then added to a sealed tube (0.08 mmol) anddissolved in 1 mL dioxane. Ammonium hydroxide (30%, 4 mL) was added andthe reaction was sealed and heated to 160° C. for 24 h after which itwas recharged with 3 mL additional ammonium hydroxide and heated for 24additional hours. The reaction was cooled, concentrated and purified viaHPLC purification to provide compound IV-26. ESI-MS m/z: 433.1 [M+H]⁺.

Example 172

A solution of dichlorothiadiazole (250 mg, 1.62 mmol, 1.1 eq.) in THF (4mL) was treated dropwise with a solution of amine I-1 (440 mg, 1.47mmol, 1 eq.) and triethylamine (250 uL, 1.6 mmol, 1.1 eq.) in THF (6mL). The reaction was monitored by LC/MS and allowed to proceed for 5 d,at which point most of the material appeared to be converted and thereaction mixture was diluted with DCM, 2-3 g of silica gel added, andconcentrated in vacuo. Purification of this material by flashchromatography (gradient of 30-100% ethyl acetate/hexanes) affordedcompound IV-27 as a white solid (540 mg, 88% yield). ESI-MS m/z: 417.11[M+H]⁺.

TABLE 3 In Vitro IC₅₀ data for selected compounds. Greater than 1 μM toIC₅₀ (nM) Greater than 10 μM 10 μM 1 μM to 100 nM Less than 100 nM PI3Kδ I-53, I-54, I-55, I- I-30, I-46, I-52, I- I-6, I-27, I-35, I-37, I-2,I-4, I-14, I-16, 62, I-71, I-72, I-77, 68, I-99, I-100, I- I-39, I-93,I-95, I- I-18, I-20, I-21, I- III-26, III-29, III- 102, 98, I-101,I-106, 23, I-24, I-25, I-29, 37, III-43, III-47, II-13, II-28, II-29,II-16, II-21, II-23, I-33, I-36, I-38, I- III-48, II-31, II-32, II-33,II-44, 40, I-41, I-42, I-43, IV-1, IV-3, IV-4, III-22, III-28, III-14,III-40, I-44, I-45, I-47, I- IV-5, IV-6, IV-8, IV-7, IV-9, IV-14, IV-2,IV-21, IV-22 48, I-49, I-50, I-51, IV-10, IV-25, IV- IV-19, IV-20, IV-23I-57, I-58, I-59, I- 26, IV-27 63, I-65, I-70, I-73, I-74, I-75, I-76,I- 78, I-79, I-80, I-81, I-82, I-83, I-84, I- 85, I-86, I-87, I-88,I-89, I-90, I-91, I- 92, I-94, I-96, I-97, I-103, II-2, II-4, II-5,II-7, II-8, II-9, II-10, II- 11, II-14, II-17, II- 18, II-20, II-22, II-24, II-30, II-45, II- 47, II-48, II-49, II- 50, III-3, III-4, III-5,III-6, III-8, III-10, III-11, III-12, III- 13, III-15, III-17, III-18,III-19, III- 20, III-21, III-23, III-24, III-25, III- 27, III-30,III-31, III-32, III-36, III- 39, III-41, III-42, III-44, III-45, III-46, III-49, IV-11, IV-12, IV- 13, IV-24 PI3K γ I-68, I-71, I-72, I- I-6,I-27, I-46, I-53, I-33, I-37, I-39, I- I-2, I-4, I-14, I-16, 77, I-99,I-54, I-55, I-100, I- 44, I-62, I-65, I-73, I-18, I-20, I-21, I- II-28,II-29, 106, I-93, I-97, I-98, I- 23, I-24, I-25, I-29, III-28, III-47,III- II-8, II-13, II-31, II- 102, I-30, I-35, I-36, I- 48, 32, II-33,II-44, II-7, II-9, II-11, II- 38, I-40, I-41, I-42, IV-1, IV-3, IV-4,III-14, III-26, III- 16, II-21, II-23, II- I-43, I-45, I-47, I- IV-5,IV-6, IV-7, 29, III-37, III-40, 30, II-45, II-47, II- 48, I-49, I-50,I-51, IV-8, IV-9, IV-10, III-41, III-43, 48, II-50, I-52, I-57, I-58, I-IV-14, IV-19, IV- IV-2, IV-20 III-22, IV-21 59, I-63, I-70, I-74, 23,IV-25, IV-26, I-75, I-76, I-78, I- IV-27 79, I-80, I-81, I-82, I-83,I-84, I-85, I- 86, I-87, I-88, I-89, I-90, I-91, I-92, I- 94, I-95,I-96, I- 101, I-103, II-2, II-4, II-5, II- 10, II-14, II-17, II- 18,II-20, II-22, II- 24, II-49, III-3, III-4, III-5, III-6, III-8, III-10,III-11, III-12, III- 13, III-15, III-17, III-18, III-19, III- 20,III-21, III-23, III-24, III-25, III- 27, III-30, III-31, III-32, III-36,III- 39, III-42, III-44, III-45, III-46, III- 49, IV-11, IV-12, IV- 13,IV-22, IV-24 PI3K α I-27, I-30, I-33, I- I-2, I-4, I-6, I-18, I- I-14,I-16, I-20, I- 35, I-37, I-39, I-41, 21, I-24, I-25, I-29, 23, I-40,I-45, I-58, I-42, I-46, I-52, I- I-36, I-38, I-43, I- I-63, I-75, I-76,I- 53, I-54, I-55, I-57, 44, I-47, I-48, I-49, 81, I-82, I-83, I-85,I-59, I-62, I-65, I- I-50, I-51, I-70, I- I-88, I-90, I-92, I- 68, I-71,I-72, I-77, 73, I-74, I-79, I-80, 94, I-103, I-78, I-93, I-95, I- I-84,I-86, I-87, I- II-10, 97, I-98, I-99, I-100, 89, I-91, I-96, I-106,III-5, III-17, III-40, I-101, I-102, II-2, II-4, II-5, II-7, IV-24II-13, II-16, II-21, II-8, II-9, II-11, II- II-23, II-28, II-29, 14,II-17, II-18, II- II-30, II-31, II-32, 20, II-22, II-24, II- II-33,II-44, II-47, 45, II-48, II-49, II-50, III-3, III-4, III-6, III-11,III-14, III- III-8, III-10, III-12, 19, III-21, III-22, III-13, III-15,III- III-24, III-26, III- 18, III-20, III-23, 28, III-29, III-31,III-25, III-27, III- III-32, III-37, III- 30, III-36, III-39, 41,III-42, III-43, III-44, III-45, III- III-46, III-47, III- 49, 48, IV-12,IV-13 IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, IV-10,IV-11, IV- 14, IV-19, IV-20, IV-21, IV-22, IV- 23, IV-25, IV-26, IV-27PI3K β I-6, I-21, I-25, I-27, I-4, I-18, I-24, I-40, I-2, I-14, I-16,I-20, I-23, I-92, I-103, I-30, I-35, I-36, I- I-50, I-51, I-58, I- I-29,I-33, I-49, I- II-10, 37, I-38, I-39, I-41, 65, I-63, I-70, I-74, 83,I-90, III-5, III-17, I-42, I-43, I-44, I- I-75, I-76, I-79, I- II-2,II-7, II-11, II- IV-24 45, I-46, I-47, I-48, 81, I-82, I-85, I-88, 14,II-20, II-22, II- I-52, I-53, I-54, I- I-93, I-94, I-96, I- 24, 55,I-57, I-59, I-62, 106, III-3, III-4, III-6, I-68, I-71, I-72, I- II-4,II-5, II-8, II- III-8, III-10, III-19, 73, I-77, I-78, I-80, 18, II-28,II-29, II- III-20, III-23, III- I-84, I-86, I-87, I- 30, II-44, II-45,II- 27, III-30, III-36, 89, I-91, I-95, I-97, 49, III-39, III-40, III-I-98, I-99, I-100, I- III-11, III-12, III- 44, III-45, III-49, 101,I-102, 13, III-15, III-18, IV-12 II-9, II-13, II-16, II- III-21, III-24,III- 17, II-21, II-23, II- 25, III-31, III-32, 31, II-32, II-33, II-III-46, 47, II-48, II-50, IV-11, IV-13, IV-22 III-14, III-22, III- 26,III-28, III-29, III-37, III-41, III- 42, III-43, III-47, III-48, IV-1,IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV-14, IV- 19,IV-20, IV-21, IV-23, IV-25, IV- 26, IV-27 B cell proliferation I-99,I-100 I-6, I-27, I-52, I-95, I-2, I-4, I-14, I-16, EC₅₀ (nM) I-98, I-18,I-20, I-21, I- III-46 23, I-24, I-25, I-33, I-38, I-40, I-41, I- 42,I-43, I-48, I-49, I-50, I-51, I-57, I- 58, I-59, I-63, I-70, I-73, I-74,I-75, I- 76, I-78, I-79, I-80, I-81, I-82, I-83, I- 84, I-85, I-86,I-87, I-88, I-89, I-90, I- 91, I-96, I-97, I- 101, II-2, II-4, II-5,II-7, II-9, II-10, II-11, II-14, II-17, II-18, II-30, II-45, II-49,II-50, III-3, III-4, III-5, III-6, III-8, III-10, III-11, III-12, III-13, III-15, III-17, III-27, III-30, III- 31, III-36, III-39, III-41,III-42, III- 44, III-45, III-49, IV-2, IV-11, IV-22, IV-24

TABLE 4 Structures of the Compounds for the IC₅₀ results described inTable 3 above. Structure

Compound I-2

Compound I-4

Compound I-6

Compound I-14

Compound I-16

Compound I-18

Compound I-20

Compound I-21

Compound I-23

Compound I-24

Compound I-25

Compound I-27

Compound I-29

Compound I-30

Compound I-33

Compound I-35

Compound I-36

Compound I-37

Compound I-38

Compound I-39

Compound I-40

Compound I-41

Compound I-42

Compound I-43

Compound I-44

Compound I-45

Compound I-46

Compound I-47

Compound I-48

Compound I-49

Compound I-50

Compound I-51

Compound I-52

Compound I-53

Compound I-54

Compound I-55

Compound I-57

Compound I-58

Compound I-59

Compound I-62

Compound I-63

Compound I-65

Compound I-68

Compound I-70

Compound I-71

Compound I-72

Compound I-73

Compound I-74

Compound I-75

Compound I-76

Compound I-77

Compound I-78

Compound I-79

Compound I-80

Compound I-81

Compound I-82

Compound I-83

Compound I-84

Compound I-85

Compound I-86

Compound I-87

Compound I-88

Compound I-89

Compound I-90

Compound I-91

Compound I-92

Compound I-93

Compound I-94

Compound I-95

Compound I-96

Compound I-97

Compound I-98

Compound I-99

Compound I-100

Compound I-101

Compound I-102

Compound I-103

Compound I-106

Compound I-107

Compound II-2

Compound II-4

Compound II-5

Compound II-7

Compound II-8

Compound II-9

Compound II-10

Compound II-11

Compound II-13

Compound II-14

Compound II-16

Compound II-17

Compound II-18

Compound II-20

Compound II-21

Compound II-22

Compound II-23

Compound II-24

Compound II-28

Compound II-29

Compound II-30

Compound II-31

Compound II-32

Compound II-33

Compound II-44

Compound II-45

Compound II-47

Compound II-48

Compound II-49

Compound II-50

Compound III-3

Compound III-4

Compound III-5

Compound III-6

Compound III-8

Compound III-10

Compound III-11

Compound III-12

Compound III-13

Compound III-14

Compound III-15

Compound III-17

Compound III-18

Compound III-19

Compound III-20

Compound III-21

Compound III-22

Compound III-23

Compound III-24

Compound III-25

Compound III-26

Compound III-27

Compound III-28

Compound III-29

Compound III-30

Compound III-31

Compound III-32

Compound III-36

Compound III-37

Compound III-39

Compound III-40

Compound III-41

Compound III-42

Compound III-43

Compound III-44

Compound III-45

Compound III-46

Compound III-47

Compound III-48

Compound III-49

Compound IV-1

Compound IV-2

Compound IV-3

Compound IV-4

Compound IV-5

Compound IV-6

Compound IV-7

Compound IV-8

Compound IV-9

Compound IV-10

Compound IV-11

Compound IV-12

Compound IV-13

Compound IV-14

Compound IV-19

Compound IV-20

Compound IV-21

Compound IV-22

Compound IV-23

Compound IV-24

Compound IV-25

Compound IV-26

Compound IV-27Biological Activity Assessment

A PI3-Kinase HTRF® assay kit (cat No. 33-016) purchased from MilliporeCorporation was used to screen compounds provided herein. This assayused specific, high affinity binding of the GRP1 pleckstrin homology(PH) domain to PIP3, the product of a Class 1A or 1B PI3 Kinase actingon its physiological substrate PIP2. During the detection phase of theassay, a complex was generated between the GST-tagged PH domain andbiotinylated short chain PIP3. The biotinylated PIP3 and the GST-taggedPH domain recruited fluorophores (Streptavidin-Allophycocyanin andEuropium-labeled anti-GST respectively) to form the fluorescenceresonance energy transfer (FRET) architecture, generating a stabletime-resolved FRET signal. The FRET complex was disrupted in acompetitive manner by non-biotinylated PIP3, a product formed in the PI3Kinase assay.

PI3 Kinase α, β, γ and δ activity was assayed using the PI3 Kinase HTRF®assay kit (catalogue No. 33-016) purchased from Millipore Corporation.Purified recombinant PI3Kα (catalogue No. 14-602-K), PI3Kβ (catalogueNo. 14-603-K), PI3Kγ (catalogue No. 14-558-K) and PI3Kδ (catalogue No.14-604-K) were obtained from Millipore Corporation. Purified recombinantPI3K enzyme was used to catalyze the phosphorylation ofphosphatidylinositol 4,5-bisphosphate (PIP2 at 10 μM) tophosphatidylinositol 3,4,5-trisphosphate (PIP3) in the presence of 10 μMATP. The assay was carried out in 384-well format and detected using aPerkin Elmer EnVision Xcite Multilabel Reader. Emission ratios wereconverted into percent inhibitions and imported into GraphPad Prismsoftware. The concentration necessary to achieve inhibition of enzymeactivity by 50% (IC₅₀) was calculated using concentrations ranging from20 μM to 0.1 nM (12-point curve). IC₅₀ values were determined using anonlinear regression model available in GraphPad Prism 5.

Example 173 Chemical Stability

The chemical stability of one or more subject compounds is determinedaccording to standard procedures known in the art. The following detailsan exemplary procedure for ascertaining chemical stability of a subjectcompound. The default buffer used for the chemical stability assay isphosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can beused. A subject compound is added from a 100 μM stock solution to analiquot of PBS (in duplicate) to give a final assay volume of 400 μL,containing 5 μM test compound and 1% DMSO (for half-life determination atotal sample volume of 700 μL is prepared). Reactions are incubated,with shaking, for 24 hours at 37° C.; for half-life determinationsamples are incubated for 0, 2, 4, 6, and 24 hours. Reactions arestopped by adding immediately 100 μL of the incubation mixture to 100 μLof acetonitrile and vortexing for 5 minutes. The samples are then storedat −20° C. until analysis by HPLC-MS/MS. Where desired, a controlcompound or a reference compound such as chlorambucil (5 μM) is testedsimultaneously with a subject compound of interest, as this compound islargely hydrolyzed over the course of 24 hours. Samples are analyzed via(RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLCconditions consist of a binary LC pump with autosampler, a mixed-mode,C12, 2×20 mm column, and a gradient program. Peak areas corresponding tothe analytes are recorded by HPLC-MS/MS. The ratio of the parentcompound remaining after 24 hours relative to the amount remaining attime zero, expressed as percent, is reported as chemical stability. Incase of half-life determination, the half-life is estimated from theslope of the initial linear range of the logarithmic curve of compoundremaining (%) vs. time, assuming first order kinetics.

Example 174 Expression and Inhibition Assays of p110α/p85α, p110β/p85α,p110δ/p85α, and p110γ

Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC₅₀ values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay. Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl2), and freshly sonicated phosphatidylinositol (100 μg/ml).Reactions are initiated by the addition of ATP containing 10 μi ofγ-32P-ATP to a final concentration of 10 or 100 μM and allowed toproceed for 5 minutes at room temperature. For TLC analysis, reactionsare then terminated by the addition of 105 μl 1N HCl followed by 160 μlCHCl₃:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged,and the organic phase is transferred to a new tube using a gel loadingpipette tip precoated with CHCl₃. This extract is spotted on TLC platesand developed for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC₅₀ determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including, but notlimited to, PI 3-Kinase ∘, β, δ, and γ. An exemplary system is PI3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried outaccording to the procedures suggested by the manufacturer. Briefly, theassay is a time resolved FRET assay that indirectly measures PIP3product formed by the activity of a PI3-K. The kinase reaction isperformed in a microtiter plate (e.g., a 384 well microtiter plate). Thetotal reaction volume is approximately 20 μl per well. In the firststep, each well receives 2 μl of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, approximately 14.5 μlof a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added perwell for a final concentration of 0.25-0.3 μg/ml kinase and 10 μM PIP2.The plate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 μl of ATP (diluted in 1× reaction buffer) isadded per well for a final concentration of 10 μM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 μl of Stop Solution per well and then 5 μl ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC₅₀s are generated using GraphPad Prism 5.

Example 175 B Cell Activation and Proliferation Assay

The ability of one or more subject compounds to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing Alamar Blue reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 μl at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 μM bME+5mM HEPES). A compound provided herein is diluted in B Cell Media andadded in a 10 μl volume. Plates are incubated for 30 min at 37° C. and5% CO₂ (0.2% DMSO final concentration). A 50 μl B cell stimulationcocktail is then added containing either 10 μg/ml LPS or 5 μg/ml F(ab′)2Donkey anti-mouse 1 μM plus 2 ng/ml recombinant mouse IL4 in B CellMedia. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 15 μL of Alamar Blue reagent is added to each well and plates areincubated for 5 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ or EC₅₀ values are calculated usingGraphPad Prism 5.

Example 176 Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation can be determined according to standard procedures knownin the art. For instance, an in vitro cellular proliferation assay canbe performed to measure the metabolic activity of live cells. The assayis performed in a 96 well microtiter plate using Alamar Blue reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 μl at 5,000 cells/well in Tumor Cell Media. A compoundprovided herein is diluted in Tumor Cell Media and added in a 10 μlvolume. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 10 μL of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ values are calculated using GraphPad Prism5.

Example 177 Antitumor Activity In Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-Refractory Tumor Models

1. Clinically-Derived Ovarian Carcinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient. The compounds describedherein are administered to nude mice bearing staged tumors using anevery 2 days×5 schedule.

2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein. The compoundsdescribed herein can be administered to mice bearing staged tumors on anevery 2 days×5 schedule.

3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel. Thecompounds described herein can be administered to mice bearing stagedtumors on an every 2 days×5 schedule.

4. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. The compounds described herein can be administeredto mice bearing staged tumors on an every 2 days×5 schedule.

One or more compounds as provided herein can be used in combinationother therapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known the art includingthose described herein.

Example 178 Microsome Stability Assay

The stability of one or more subject compounds is determined accordingto standard procedures known in the art. For example, stability of oneor more subject compounds is established by an in vitro assay. Forexample, an in vitro microsome stability assay is established thatmeasures stability of one or more subject compounds when reacting withmouse, rat or human microsomes from liver. The microsome reaction withcompounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/ml mouse, rat or human livermicrosome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH₂O.Negative control (without NADPH) tube contains 75 μL of 20.0 mg/mlmouse, rat or human liver microsome; 0.4 mL of 0.2 M phosphate buffer,and 525 mL of ddH₂O. The reaction is started by adding 1.0 mL of 10.0 mMtested compound. The reaction tubes are incubated at 37° C. 100 μLsample is collected into new Eppendorf tube containing 300 mL coldmethanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples arecentrifuged at 15,000 rpm to remove protein. Supernatant of centrifugedsample is transferred to new tube. Concentration of stable compoundafter reaction with microsome in the supernatant is measured by LiquidChromatography/Mass Spectrometry (LC-MS).

Example 179 Plasma Stability Assay

The stability of one or more subject compounds in plasma is determinedaccording to standard procedures known in the art. See, e.g., RapidCommun. Mass Spectrom., 10: 1019-1026. The following procedure is anHPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A subject compound is added from a 400 μM stocksolution to an aliquot of pre-warmed plasma to give a final assay volumeof 400 μL (or 800 μL for half-life determination), containing 5 μM testcompound and 0.5% DMSO. Reactions are incubated, with shaking, for 0minutes and 60 minutes at 37° C., or for 0, 15, 30, 45 and 60 minutes at37 C for half life determination. Reactions are stopped by transferring50 μL of the incubation mixture to 200 μL of ice-cold acetonitrile andmixed by shaking for 5 minutes. The samples are centrifuged at 6000×gfor 15 minutes at 4° C. and 120 μL of supernatant removed into cleantubes. The samples are then evaporated to dryness and submitted foranalysis by HPLC-MS/MS.

In one embodiment, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 180 Kinase Signaling in Blood

PI3K/Akt/mTor signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. (2007) 434:131-54). This method is by nature asingle cell assay so that cellular heterogeneity can be detected ratherthan population averages. This allows concurrent distinction ofsignaling states in different populations defined by other markers.Phosflow is also highly quantitative. To test the effects of one or morecompounds provided herein, unfractionated splenocytes, or peripheralblood mononuclear cells are stimulated with anti-CD3 to initiate T-cellreceptor signaling. The cells are then fixed and stained for surfacemarkers and intracellular phosphoproteins. Inhibitors provided hereininhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6, whereasrapamycin inhibits S6 phosphorylation and enhances Akt phosphorylationunder the conditions tested.

Similarly, aliquots of whole blood are incubated for 15 minutes withvehicle (e.g., 0.1% DMSO) or kinase inhibitors at variousconcentrations, before addition of stimuli to cross link the T cellreceptor (TCR) (anti-CD3 with secondary antibody) or the B cell receptor(BCR) using anti-kappa light chain antibody (Fab′2 fragments). Afterapproximately 5 and 15 minutes, samples are fixed (e.g., with cold 4%paraformaldehyde) and used for phosflow. Surface staining is used todistinguish T and B cells using antibodies directed to cell surfacemarkers that are known to the art. The level of phosphorylation ofkinase substrates such as Akt and S6 are then measured by incubating thefixed cells with labeled antibodies specific to the phosphorylatedisoforms of these proteins. The population of cells are then analyzed byflow cytometry.

Example 181 Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) patientsupon initial diagnosis or relapse. Live cells are isolated and enrichedfor CD19+ CD34+ B cell progenitors. After overnight liquid culture,cells are plated in methocult GF+ H4435, Stem Cell Technologies)supplemented with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3ligand, and erythropoietin) and various concentrations of knownchemotherapeutic agents in combination with either compounds of thepresent disclosure. Colonies are counted by microscopy 12-14 days later.This method can be used to test for evidence of additive or synergisticactivity.

Example 182 In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5 Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g., Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells are administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days are euthanizedand lymphoid organs are harvested for analysis. Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors are given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabeled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompounds provided herein in combination with known chemotherapeuticagents can reduce leukemic blood cell counts as compared to treatmentwith known chemotherapeutic agents (e.g., Gleevec) alone under theconditions tested.

Example 183 Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R2KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus patients show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R2KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Sle1z.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

The NZB/W F1 mice spontaneously develop a systemic autoimmune diseasewith that is a model of lupus. The mice are treated starting at 20 weeksof age for a prophylactic model and at 23 weeks of age for a therapeuticmodel. Blood and urine samples are obtained at approximately throughoutthe testing period, and tested for antinuclear antibodies (in dilutionsof serum) or protein concentration (in urine). Serum is also tested foranti-ssDNA and anti-dsDNA antibodies by ELISA. Glomerulonephritis isassessed in kidney sections stained with H&E at the end of the study, orsurvival can be an endpoint. For example, the proteozome inhibitorBortezimib is effective at blocking disease in the NZB/W model in boththe profilactic and therapeutic model with reductions in auto-antibodyproduction, kidney damage, and improvements in survival (Nature Medicine14, 748-755 (2008)).

Lupus disease model mice such as R2KO, BXSB or MLR/lpr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of vehicle, RAD001 at about 10 mg/kg, or compounds provided hereinat approximately 1 mg/kg to about 500 mg/kg. Blood and urine samples areobtained at approximately throughout the testing period, and tested forantinuclear antibodies (in dilutions of serum) or protein concentration(in urine). Serum is also tested for anti-ssDNA and anti-dsDNAantibodies by ELISA. Animals are euthanized at day 60 and tissuesharvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This established art model can be employed to demonstrate that thekinase inhibitors provided herein can suppress or delay the onset oflupus symptoms in lupus disease model mice.

Example 184 Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from a γ ray source. About1 hr after the radiation dose, mice are injected with about 1×10⁶leukemic cells from early passage p190 transduced cultures (e.g., asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×10⁶ normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e.g., imatinib at about 70 mg/kg twicedaily). For the first phase p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect pAkt-S473 and pS6-S235/236 in hCD4-gated cells without prior sorting.These signaling studies are particularly useful if, for example,drug-treated mice have not developed clinical leukemia at the 35 daytime point. Kaplan-Meier plots of survival are generated and statisticalanalysis done according to methods known in the art. Results from p190cells are analyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μl) are obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein.

This general assay known in the art can be used to demonstrate thateffective therapeutic doses of the compounds provided herein can be usedfor inhibiting the proliferation of leukemic cells.

Example 185 Matrigel Plug Angiogenesis Assay

Matrigel containing test compounds are injected subcutaneously orintraocularly, where it solidifies to form a plug. The plug is recoveredafter 7-21 days in the animal and examined histologically to determinethe extent to which blood vessels have entered it. Angiogenesis ismeasured by quantification of the vessels in histologic sections.Alternatively, fluorescence measurement of plasma volume is performedusing fluorescein isothiocyanate (FITC)-labeled dextran 150. The resultsare expected to indicate one or more compounds provided herein thatinhibit angiogenesis and are thus expected to be useful in treatingocular disorders related to aberrant angiogenesis and/or vascularpermeability.

Example 186 Corneal Angiogenesis Assay

A pocket is made in the cornea, and a plug containing an angiogenesisinducing formulation (e.g., VEGF, FGF, or tumor cells), when introducedinto this pocket, elicits the ingrowth of new vessels from theperipheral limbal vasculature. Slow-release materials such as ELVAX(ethylene vinyl copolymer) or Hydron are used to introduce angiogenesisinducing substances into the corneal pocket. Alternatively, a spongematerial is used.

The effect of putative inhibitors on the locally induced (e.g., spongeimplant) angiogenic reaction in the cornea (e.g., by FGF, VEGF, or tumorcells). The test compound is administered orally, systemically, ordirectly to the eye. Systemic administration is by bolus injection or,more effectively, by use of a sustained-release method such asimplantation of osmotic pumps loaded with the test inhibitor.Administration to the eye is by any of the methods described hereinincluding, but not limited to eye drops, topical administration of acream, emulsion, or gel, intravitreal injection.

The vascular response is monitored by direct observation throughout thecourse of the experiment using a stereomicroscope in mice. Definitivevisualization of the corneal vasculature is achieved by administrationof fluorochrome-labeled high-molecular weight dextran. Quantification isperformed by measuring the area of vessel penetration, the progress ofvessels toward the angiogenic stimulus over time, or in the case offluorescence, histogram analysis or pixel counts above a specific(background) threshold.

The results can indicate one or more compounds provided herein inhibitangiogenesis and thus can be useful in treating ocular disorders relatedto aberrant angiogenesis and/or vascular permeability.

Example 187 Microtiter-Plate Angiogenesis Assay

The assay plate is prepared by placing a collagen plug in the bottom ofeach well with 5-10 cell spheroids per collagen plug each spheroidcontaining 400-500 cells. Each collagen plug is covered with 1100 μl ofstorage medium per well and stored for future use (1-3 days at 37° C.,5% CO₂). The plate is sealed with sealing. Test compounds are dissolvedin 200 μl assay medium with at least one well including a VEGF positivecontrol and at least one well without VEGF or test compound as anegative control. The assay plate is removed from the incubator andstorage medium is carefully pipeted away. Assay medium containing thetest compounds are pipeted onto the collagen plug. The plug is placed ina humidified incubator for (37° C., 5% CO₂) 24-48 hours. Angiogenesis isquantified by counting the number of sprouts, measuring average sproutlength, or determining cumulative sprout length. The assay can bepreserved for later analysis by removing the assay medium, adding 1 mlof 10% paraformaldehyde in Hanks BSS per well, and storing at 4° C. Theresults are expected to identify compounds that inhibit angiogenesis invarious cell types tested, including cells of ocular origin.

Example 188 Combination use of PI3K-δ Inhibitors and Agents that InhibitIgE Production or Activity

The compounds as provided herein can present synergistic or additiveefficacy when administered in combination with agents that inhibit IgEproduction or activity. Agents that inhibit IgE production include, forexample, one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e., rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as Omalizumab and TNX-901.

One or more of the subject compounds capable of inhibiting PI3K-δ can beefficacious in treatment of autoimmune and inflammatory disorders(AIID), for example, rheumatoid arthritis. If any of the compoundscauses an undesired level of IgE production, one can choose toadminister it in combination with an agent that inhibits IgE productionor IgE activity. Additionally, the administration of PI3K-δ or PI3K-δ/γinhibitors as provided herein in combination with inhibitors of mTOR canalso exhibit synergy through enhanced inhibition of the PI3K pathway.Various in vivo and in vitro models can be used to establish the effectof such combination treatment on AIID including, but not limited to (a)in vitro B-cell antibody production assay, (b) in vivo TNP assay, and(c) rodent collagen induced arthritis model.

(a) B-Cell Assay

Mice are euthanized, and the spleens are removed and dispersed through anylon mesh to generate a single-cell suspension. The splenocytes arewashed (following removal of erythrocytes by osmotic shock) andincubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads(Miltenyi Biotec). The bead-bound cells are separated from unbound cellsusing a magnetic cell sorter. The magnetized column retains the unwantedcells and the resting B cells are collected in the flow-through.Purified B-cells are stimulated with lipopolysaccharide or an anti-CD40antibody and interleukin 4. Stimulated B-cells are treated with vehiclealone or with PI3K-δ inhibitors as provided herein with and without mTORinhibitors such as rapamycin, rapalogs, or mTORC1/C2 inhibitors. Theresults are expected to show that in the presence of mTOR inhibitors(e.g., rapamycin) alone, there is little to no substantial effect on IgGand IgE response. However, in the presence of PI3K-δ and mTORinhibitors, the B-cells are expected to exhibit a decreased IgG responseas compared to the B-cells treated with vehicle alone, and the B-cellsare expected to exhibit a decreased IgE response as compared to theresponse from B-cells treated with PI3K-δ inhibitors alone.

(b) TNP Assay

Mice are immunized with TNP-Ficoll or TNP-KHL and treated with: vehicle,a PI3K-δ inhibitor, an mTOR inhibitor, for example rapamycin, or aPI3K-δ inhibitor in combination with an mTOR inhibitor such asrapamycin. Antigen-specific serum IgE is measured by ELISA using TNP-BSAcoated plates and isotype specific labeled antibodies. It is expectedthat mice treated with an mTOR inhibitor alone exhibit little or nosubstantial effect on antigen specific IgG3 response and nostatistically significant elevation in IgE response as compared to thevehicle control. It is also expected that mice treated with both PI3K-δinhibitor and mTOR inhibitor exhibit a reduction in antigen specificIgG3 response as compared to the mice treated with vehicle alone.Additionally, the mice treated with both PI3K-δ inhibitor and mTORinhibitor exhibit a decrease in IgE response as compared to the micetreated with PI3K-δ inhibitor alone.

(c) Rat Collagen Induced Arthritis Model

Female Lewis rats are anesthetized and given collagen injectionsprepared and administered as described previously on day 0. On day 6,animals are anesthetized and given a second collagen injection. Calipermeasurements of normal (pre-disease) right and left ankle joints areperformed on day 9. On days 10-11, arthritis typically occurs and ratsare randomized into treatment groups. Randomization is performed afterankle joint swelling is obviously established and there is good evidenceof bilateral disease.

After an animal is selected for enrollment in the study, treatment isinitiated. Animals are given vehicle, PI3K-δ inhibitor, or PI3K-δinhibitor in combination with rapamycin. Dosing is administered on days1-6. Rats are weighed on days 1-7 following establishment of arthritisand caliper measurements of ankles taken every day. Final body weightsare taken on day 7 and animals are euthanized.

The combination treatment using a compound as provided herein andrapamycin can provide greater efficacy than treatment with PI3K-δinhibitor alone.

Certain compounds provided herein (e.g., Compounds I-21, I-86, I-87,I-91, and III-13) were tested in the rat Collagen Induced ArthritisModel using procedures substantially similar to those described above,and all of the tested compounds demonstrated EC₅₀ values of less than 50mg/kg.

Example 189 Delayed Type Hypersensitivity Model

DTH was induced by sensitizing 60 BALB/c male mice on day 0 and day 1with a solution of 0.05% 2,4 dinitrofluorobenzene (DNFB) in a 4:1acetone/olive oil mixture. Mice were gently restrained while 20 μL ofsolution was applied to the hind foot pads of each mouse. The hind footpads of the mice were used as they represent an anatomical site that canbe easily isolated and immobilized without anesthesia. On day 5, micewere administered a single dose of vehicle, a compound provided hereinat 10, 3, 1, or 0.3 mg/kg, or dexamethasone at a dose of 5 mg/kg by oralgavage. Thirty minutes later mice were anaesthetized, and a solution of0.25% DNFB in a 4:1 acetone/olive oil solution was applied to the leftinner and outer ear surface. This application resulted in the inductionof swelling to the left ear and under these conditions, all animalsresponded to this treatment with ear swelling. A vehicle controlsolution of 4:1 acetone/olive oil was applied to the right inner andouter ear. Twenty four hours later, mice were anaesthetized, andmeasurements of the left and right ear were taken using a digitalmicrometer. The difference between the two ears was recorded as theamount of swelling induced by the challenge of DNFB. Drug treatmentgroups were compared to vehicle control to generate the percentreduction in ear swelling. Dexamethasone is routinely used as a positivecontrol as it has broad anti-inflammatory activity.

Example 190 Peptidoglycan-Polysaccharide Rat Arthritic Model

(a) Systemic Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intraperitoneally (i.p.)with a single injection of purified PG-PS 10S Group A, D58 strain(concentration 25 μg/g of bodyweight) suspended in sterile 0.85% saline.Each animal receives a total volume of 500 microliters administered inthe lower left quadrant of the abdomen using a 1 milliliter syringe witha 23 gauge needle. Placement of the needle is critical to avoidinjecting the PG-PS 10S into either the stomach or caecum. Animals areunder continuous observation until fully recovered from anesthesia andmoving about the cage. An acute response of a sharp increase in anklemeasurement, typically 20% above baseline measurement can peak in 3-5days post injection. Treatment with test compounds can be PO, SC, IV orIP. Rats are dosed no more than two times in a 24 hour time span.Treatment can begin on day 0 or any day after that through day 30. Theanimals are weighed on days 0, 1, 2, 3, 4, 5, 6, 7 and beginning againon day 12-30 or until the study is terminated. Paw/ankle diameter ismeasured with a digital caliper on the left and right side on day 0prior to injection and again on day 1, 2, 3, 4, 5, 6 and 7. On day 12,measurements begin again and continue on through day 30. At this time,animals can be anesthetized with isoflurane, as described above, andterminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

(b) Monoarticular Arthritis Model

All injections are performed under anesthesia. 60 female Lewis rats(150-170) are anesthetized by inhalation isoflurane using a small animalanesthesia machine. The animals are placed in the induction chamberuntil anesthetized by delivery of 4-5% isoflurane in O₂ and then held inthat state using a nose cone on the procedure table. Maintenance levelof isoflurane is at 1-2%. Animals are injected intra-articular (i.a.)with a single injection of purified PG-PS 100P Group A, D58 strain(concentration 500 ug/mL) suspended in sterile 0.85° A saline. Each ratreceives a total volume of 10 microliters administered into thetibiotalar joint space using a 1 milliliter syringe with a 27 gaugeneedle. Animals are under continuous observation until fully recoveredfrom anesthesia and moving about the cage. Animals that respond 2-3 dayslater with a sharp increase in ankle measurement, typically 20% abovebaseline measurement on the initial i.a. injection, are included in thestudy. On day 14, all responders are anesthetized again using theprocedure previously described. Animals receive an intravenous (I.V.)injection of PG-PS (concentration 250 uL/mL). Each rat receives a totalvolume of 400 microliters administered slowly into the lateral tail veinusing a 1 milliliter syringe with a 27 gauge needle. Baseline anklemeasurements are measured prior to IV injection and continue through thecourse of inflammation or out to day 10. Treatment with test compoundswill be PO, SC, IV or IP. Rats are dosed no more than two times in a 24hour time span. Treatment can begin on day 0 or any day after thatthrough day 24. The animals are weighed on days 0, 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. Paw/anklediameter is measured with a digital caliper on the left and right sideon day 0 prior to injection and again on day 1, 2, 3, 4, 5, andbeginning again on day 14-24 or until the study is terminated. At thistime, animals can be anesthetized with isoflurane, as described above,and terminal blood samples can be obtained by tail vein draws for theevaluation of the compound blood levels, clinical chemistry orhematology parameters. Animals are them euthanized with carbon dioxideoverdose. A thoracotomy can be conducted as a means of deathverification.

Example 191 Mice Models for Asthma

Efficacy of a compound provided herein in treating, preventing and/ormanaging asthma can be assessed using an conventional animal modelsincluding various mice models described in, for example, Nials et al.,Dis Model Mech. 1(4-5): 213-220 (2008).

(a) Acute Allergen Challenge Models

Several models are known in the art and any of such models can be used.Although various allergens can be used to induce asthma-like conditions,the principle is consistent throughout the methods. Briefly, asthma-likeconditions are induced through multiple systemic administration of theallergen (e.g., ova, house dust mite extracts and cockroach extracts) inthe presence of an adjuvant such as aluminum hydroxide. Alternatively,an adjuvant-free system can be used, but it usually requires a highernumber of exposures to achieve suitable sensitization. Once induced,animals exhibit many key features of clinical asthma such as: elevatedlevels of IgE; airway inflammation; goblet cell hyperplasia; epithelialhypertrophy; AHR ro specific stimuli; and early and late phasebronchoconstriction. Potential efficacy of a compound thus can beassessed by determining whether one or more of these clinical featuresare reversed or mitigated.

(b) Chronic Allergen Challenge Models

Chronic allergen challenge models aim to reproduce more of the featuresof the clinical asthma, such as airway remodeling and persistent AHR,than acute challenge models. While allergens similar to those used inacute allergen challenge models can be used, in chronic allergenchallenge models, animals are subjected to repeated exposure of theairways to low levels of allergen for a period of up to 12 weeks. Onceinduced, animals exhibit key features of human asthma such as:allergen-dependent sensitization; a Th2-dependent allergic inflammationcharacterized by eosinophillic influx into the airway mucosa; AHR; andairway remodeling as evidenced by goblet cell hyperplasia, epithelialhypertrophy, subepithelial or peribronchiolar fibrosis. Potentialefficacy of a compound thus can be assessed by determining whether oneor more of these clinical features are reversed or mitigated.

Example 192 Models for Psoriasis

Efficacy of a compound provided herein in treating, preventing and/ormanaging psoriasis can be assessed using an conventional animal modelsincluding various animal models described in, for example, Boehncke etal., Clinics in Dermatology, 25: 596-605 (2007).

As an example, the mouse model based on adoptive transfer ofCD4⁺CD45RB^(hi) T cells described in Hong et al., J. Immunol., 162:7480-7491 (1999) can be made. Briefly, female BALB/cBY (donor) andC.B.-17/Prkdc scid/scid (recipient) mice are housed in a specificpathogen-free environment and are used between 6 and 8 weeks of age.CD4′ T cells are enriched from BALB/cBy splenocytes using a mouse CD4enrichment kit. The cells are then labeled with PE-conjugated anti-CD4,FITC-conjugated anti-CD45RB, and APC-conjugated anti-CD25 antibodies.Cells are sorted using a cell sorter. CD4⁺CD45RB^(hi)CD25 cells arecollected. Cells are resuspended in saline and 4×10⁸ cells/mouse areinjected i.p. into C.B.-17/Prkdc scid/scid mice. Mice may be dosed withLPS, cytokines, or antibodies as necessary. Mice are monitored forexternal signs of skin lesions twice each week. After the termination,ear, back skin, lymph nodes and spleen may be collected for further exvivo studies.

Example 193 Models for Scleroderma

A compound's efficacy in treating scleroderma can be tested using animalmodels. An exemplary animal model is a mouse model for sclerodermainduced by repeated local injections of bleomycin (“BLM”) described, forexample, in Yamamoto et al., J Invest Dermatol 112: 456-462 (1999), theentirety of which is incorporated herein by reference. This mouse modelprovides dermal sclerosis that closely resembles systemic sclerosis bothhistologically and biochemically. The sclerotic changes observed in themodel include, but are not limited to: thickened and homogenous collagenbundles and cellular filtrates; gradual increase in number of mastcells; degranulation of mast cells; elevated histamine release; increasein hydroxyproline in skin; presence of anti-nuclear antibody in serum;and strong expression of transforming growth factor β-2 mRNA. Therefore,efficacy of a compound in treating scleroderma can be assessed bymonitoring the lessening of one or more of these changes.

Briefly, the following exemplary procedures can be used to generate themouse model for scleroderma: Specific pathogen-free, female BALB/C miceand C3H mice of 6 weeks old, weighing about 20 g, are purchased andmaintained with food and water ad libitum. BLM is dissolved in PBS atdiffering concentrations and sterilized with filtration. Aliquots ofeach concentration of BLM or PBS are injected subcutaneously into theshaved back of the mice daily for 1-4 weeks with a needle.Alternatively, mice are injected every other day.

Histolopathological and biochemical changes induced can be assessedusing any methods commonly practiced in the field. For example,histopathological changes can be assessed using a standardavidine-biotin peroxidase technique with anti-L3T4 monoclonal antibody,anti-Lyt2 monoclonal antibody, anti-mouse pan-tissue-fixed macrophageantibody, anti-stem cell factor monoclonal antibody, anti-transforminggrowth factor-β polyclonal antibody, and anti-decorin antibody. Cytokineexpression of cellular infiltrates can be assessed by using severalanti-cytokine antibodies. Hydroxyproline level can be assessed byhydrolyzing skin pieces with hydrochloric acid, neutralizing with sodiumhydroxide, and colorimetrically assessing the hydrolates at 560 nm withp-dimethylaminobenzaldehyde. Pepsin-resistant collagen can be assessedby treating collagen sample extracted from biopsied tissues andanalyzing by polyacrylamide stacking gel electrophoresis. Mast cells canbe identified by toluidine blue, and cells containing matachromaticgranules can be counted under high magnification of a light microscope.Serum levels of various cytokines can be assessed by enzyme-linkedimmunosorbent assay, and mRNA levels of the cytokines can be assessed byreverse-transcriptase polymerase chain reaction. Autoantibodies in serumcan be detected using 3T3 fibroblasts as the substrate for thescreening.

Example 194 Models for Myositis

A compound's efficacy in treating myositis (e.g., dermatomyositis) canbe tested using animal models known in the art. One such example is thefamilial canine dermatomyositis model described in Hargis et al., AJP120(2): 323-325 (1985). Another example is the rabbit myosin inducedmouse model described in Phyanagi et al., Arthritis & Rheumatism,60(10): 3118-3127 (2009).

Briefly, 5-week old male SJL/J mice are used. Purified myosin fromrabbit skeletal muscle (6.6 mg/ml) is emulsified with an equal amount ofFreund's complete adjuvant and 3.3 mg/ml Mycobacterium butyricum. Themice are immunized repeatedly with emulsified rabbit myosin. Oncemyositis is induced, inflammatory cell filtration and necrotic musclefiber should be evident in the model. In the muscles of animals, CD4⁺ Tcells are mainly located in the perimysum and CD8⁺ T cells are mainlylocated in the endomysium and surround non-necrotic muscle fibers. TNFα,IFNγ and perforin are up-regulated and intercellular adhesion molecule 1is increased in the muscles.

To assess the efficacy of a compound, following administration of thecompound through adequate route at specified dose, the mice are killedand muscle tissues are harvested. The muscle tissue is immediatelyfrozen in chilled isopentane precooled in liquid nitrogen, and thencryostat sections are prepared. The sections are stained withhematoxylin and eosin for counting of number of infiltrated cells. Threesections from each mouse are prepared and photomicrographs are obtained.For immunohistochemical tests, cryostat sections of muscle are dried andfixed in cold acetone at −20° C. The slides are rehydrated in PBS, andthen endogeneous peroxide activity is blocked by incubation in 1%hydrogen peroxide. The sections are incubated overnight with ratanti-mouse CD4 monoclonal antibody, rat anti-mouse CD8 monoclonalantibody, rat anti-mouse F4/80 monoclonal antibody or normal rat IgG inantibody diluent. The samples are washed with PBS and incubated withbiotin-conjugated rabbit anti-rat IgG pretreated with 5% normal mouseserum. After washing with PBS, the samples are incubated withstreptavidin-horseradish peroxidase. After washing PBS, diaminobenzidineis used for visualization.

Example 195 Models for Sjögren Syndrome

A compound's efficacy in treating Sjögren's syndrome can be tested usinganimal models known in the art, for example, those described in Chioriniet al., Journal of Autoimmunity 33: 190-196 (2009). Examples include:mouse model spontaneously developed in first filial generation of NZBmice crossed to NZW mice (see, e.g., Jonsson et al., Clin ImmunolImmunopathol 42: 93-101 (1987); mouse model induced by i.p. injection ofincomplete Freund's adjuvant (id.; Deshmukh et al., J Oral Pathol Med38: 42-27 (2009)); NOD mouse models wherein Sjögren's phenotype isdeveloped by specific genotypes (see, e.g., Cha et al., Arthritis Rheum46: 1390-1398 (2002); Kong et al., Clin Exp Rheumatol 16: 675-681(1998); Podolin et al., J Exp Med 178: 793-803 (1993); and Rasooly etal., Clin Immunol Immunopathol 81: 287-292 (1996)); mouse modeldeveloped in spontaneous lpr mutation; mouse model developed in Id3knock-out mice (see, e.g., Li et al., Immunity 21: 551-560 (2004));mouse model developed in PI3K knock-out mice (see, e.g., Oak et al.,Proc Natl Acad Sci USA 103: 16882-16887 (2006)); mouse model developedin BAFF over-expressing transgenic mice (see, e.g., Groom et al., J ClinInvest 109: 59-68 (2002)); mouse model induced by injection of Roantigen into BALB/c mice (see, e.g., Oh-Hora et al., Nat. Immunol 9:432-443 (2008)); mouse model induced by injection of carbonic anhydraseII (see, e.g., Nishimori et al., J Immunol 154: 4865-4873 (1995); mousemodel developed in IL-14 over-expressing transgenic mice (see, e.g.,Shen et al., J Immunol 177: 5676-5686 (2006)); and mouse model developedin IL-12 expressing transgenic mice (see, e.g., McGrath-Morrow et al.,Am J Physiol Lung Cell Mol Physiol 291: L837-846 (2006)).

Example 196 Models for Immune Complex Mediated Disease

The Arthus reaction is a type 3 immune response to immune complexes, andthus, can be a mechanistic model supporting therapeutic hypothesis forimmune complex mediated diseases such as rheumatoid arthritis, lupus andother autoimmune diseases. For example, PI3Kγ and δ deficient mice canbe used as experimental models of the Arthus reaction and provideassessment of therapeutic potential of a compound as to the treatment ofimmune complex mediated diseases. The Arthus reaction can be inducedusing the following exemplary procedures as described in Konrad et al.,Journal of Biological Chemistry (2008 283(48): 33296-33303.

PI3Kγ- and PI3Kδ-deficient mice are maintained under dry barrierconditions. Mice are anesthetized with ketamine and xylazine, and thetrachea is cannulated. Appropriate amount of protein G-purified anti-OVAIgG Ab is applied, and appropriate amount of OVA antigen is givenintravenously. For PI3K blocking experiments, wortmanin is givenintratracheally together with the application of anti-OVA IgG. Mice arekilled at 2-4 hours after initiation of inflammation, and desired followup assessments can be performed using methods known in the art.

Example 197 Isoform-Selective Cellular Assays

(a) PI3Kδ Selective Assay

A compound's ability in selectively inhibiting PI3Kδ can be assessedusing RAJI cells, i.e., B lymphocyte cells derived from lymphomapatients. Briefly, serum-starved RAJI cells are stimulated withanti-human IgM, thereby causing signaling through the B-cell receptors,as described in, for example, He et al., Leukemia Research (2009) 33:798-802. B-cell receptor signaling is important for the activation,differentiation, and survival of B cells and certain B-cell derivedcancers. Reduction of phospho-AKT is indicative of compounds that mayinhibit B-cell proliferation and function in certain diseases. Bymonitoring the reduction of phospho-AKT in stimulated RAJI cells (usingfor example, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kδ can be assessed.

Certain compounds provided herein (e.g., Compounds I-21, I-86, I-87,I-91, I-106, and III-13) were tested in RAJI cell model using proceduresas described above. It was found that IC₅₀ values for phospho-AKT are asfollows: Compounds I-21, I-86, I-87, I-91, I-106, and III-13 in therange of less than 100 nM.

(b) PI3Kγ Selective Assay

A compound's ability in selectively inhibiting PI3Kγ can be assessedusing RAW264.7 macrophages. Briefly, serum-starved PAW264.7 cells arestimulated with a known GPCR agonist C5a. (See, e.g., Camps et al.,Nature Medicine (2005) 11(9): 936-943). Cells can be treated with testcompounds prior to, simultaneously with, or subsequent to thestimulation by C5a. RAW 264.7 cells respond to the complement componentfragment C5a through activation of the C5a receptor, and the C5areceptor activates macrophages and induces cell migration. Testcompounds' ability to inhibit C5a-mediated AKT phosphorylation isindicative of selective inhibition of PI3Kγ. Thus, by monitoring thereduction of phospho-AKT in stimulated RAW 264.7 cells (using forexample, phospho-AKT antibodies), a compound's potential efficacy inselectively inhibiting PI3Kγ can be assessed.

Certain compounds provided herein (e.g., Compounds I-21, I-86, I-87,I-91, I-106, and III-13) were tested in RAW 264.7 cell model usingprocedures as described above. It was found that IC₅₀ values forphospho-AKT are as follows: Compounds I-86, I-87, and I-91 in the rangeof less than 100 nM; Compounds I-21, I-106, and III-13 in the range ofbetween 100 nM and 1 μM.

(c) PI3Kα Selective Assay

A compound's ability in selectively inhibiting PI3Kα can be assessedusing SKOV-3 cells, i.e., human ovarian carcinoma cell line. Briefly,SKOV-3 cells, in which mutant PI3Kα is constitutively active, can betreated with test compounds. Test compounds' ability to inhibit AKTphosphorylation in SKOV-3 cells, therefore, is indicative of selectiveinhibition of PI3Kα. Thus, by monitoring the reduction of phospho-AKT inSKOV-3 cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kα can be assessed.

Certain compounds provided herein (e.g., Compounds I-21, I-86, I-87,I-91, and III-13) were tested in SKOV-3 cell model using procedures asdescribed above. It was found that IC₅₀ values for phospho-AKT are asfollows: Compound I-87 in the range of between 100 nM and 1 μM;Compounds I-21, I-86, I-91, and III-13 in the range of between 1 μM and10 μM.

(d) PI3Kβ Selective Assay

A compound's ability in selectively inhibiting PI3Kβ can be assessedusing 786-O cells, i.e., human kidney carcinoma cell line. Briefly,786-O cells, in which PI3Kβ is constitutively active, can be treatedwith test compounds. Test compounds' ability to inhibit AKTphosphorylation in 786-O cells, therefore, is indicative of selectiveinhibition of PI3Kβ. Thus, by monitoring the reduction of phospho-AKT in786-O cells (using for example, phospho-AKT antibodies), a compound'spotential efficacy in selectively inhibiting PI3Kβ can be assessed.

Certain compounds provided herein (e.g., Compounds I-21, I-86, I-87,I-91, and III-13) were tested in 786-O cell model using procedures asdescribed above. It was found that IC₅₀ values for phospho-AKT are asfollows: Compounds I-21, I-86, I-87, I-91, and III-13 in the range ofbetween 1 μM and 10 μM.

What is claimed is:
 1. A compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or its pharmaceutically acceptable forms thereof,wherein Cy is aryl or heteroaryl substituted by 0-1 occurrences of R³and 0-3 occurrences of R⁵; W_(b) ⁵ is CR⁸or CHR⁸; R⁸ is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl,acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro; B is hydrogen,alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,aryl or heteroaryl, each of which is substituted with 0-4 occurrences ofR²; each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea or carbonate; X is absent or—(CH(R⁹))_(z)—; Y is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R⁹)—,—C(═O)—(CHR⁹)_(z)—, —C(═O)—, —N(R⁹)—C(═O)NH—, or —N(R⁹)C(R⁹)₂—; each zis independently an integer of 1, 2, 3, or 4; R³ is unsubstituted alkyl,or R³ is alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide,sulfone, sulfonamido, halo, cyano, heteroaryl, aryl, hydroxyl, or nitro;wherein each of the above substituents can be substituted with 0, 1, 2,or 3 R¹⁷; each R⁵ is independently unsubstituted alkyl, or each R⁵ isindependently alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido,amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro; eachR⁹ is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; an

W_(d) is wherein X₁ is N or CR¹⁴; wherein R¹⁰, R¹¹ R¹², R¹³, R¹⁴, andR¹⁷ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate,oxo, or NR′R″ wherein R′ and R″ are taken together with nitrogen to forma cyclic moiety.
 2. The compound of claim 1, wherein Cy is arylsubstituted with 0-1 occurrences of R³ and 0-3 occurrences of R₅.
 3. Thecompound of claim 2, wherein Cy is phenyl substituted with 1 occurrenceof R³ and 0 occurrences of R₅.
 4. The compound of claim 3, wherein thecompound of Formula (I) has a structure of Formula (IIa) or (IIb):


5. The compound of claim 4, wherein the compound of Formula (I) has astructure of Formula (IIIa) or (IIIb):


6. The compound of claim 5, wherein the compound of Formula (I) has astructure of Formula (IIIb-1):


7. The compound of claim 1, wherein Cy is heteroaryl substituted with0-1 occurrences of R³ and 0-3 occurrences of R₅.
 8. The compound ofclaim 7, wherein Cy is 5-membered heteroaryl substituted with 0-1occurrences of R³ and 0-3 occurrences of R⁵.
 9. The compound of claim 8,wherein Cy is isothiazolyl substituted with 0-1 occurrences of R³ and 0occurrence of R⁵.
 10. The compound of claim 9, wherein the compound ofFormula (I) has the structure of Formula (IVa) or Formula (IVb):


11. The compound of claim 10, wherein the compound of Formula (IVa) orFormula (IVb) has the structure of Formula (Va) or Formula (Vb):


12. The compound of claim 11, wherein the compound of Formula (I) has astructure of Formula (Va-1):


13. The compound of claim 8, wherein Cy is thiophenyl substituted with0-1 occurrences of R³ and 0 occurrence of R⁵.
 14. The compound of claim13, wherein the compound of Formula (I) has the structure of Formula(VIa) or Formula (VIb):


15. The compound of claim 14, wherein the compound of Formula (VIa) orFormula (VIb) has the structure of Formula (VIIa) or (VIIb):


16. The compound of claim 14, wherein the compound of Formula (VIa) orFormula (VIb) has the structure of Formula (VIIIa) or Formula (VIIIb):


17. The compound of claim 16, wherein the compound of Formula (VIIa) orFormula (VIIb) has the structure of Formula (IXa) or Formula (IXb):


18. The compound of claim 17, wherein the compound of Formula (I) has astructure of Formula (IXa-1):


19. The compound of claim 1, wherein each R⁵ is independently selectedfrom CH₃, OCH₃, and halo.
 20. The compound of claim
 1. wherein R³ isunsubstituted alkyl or R³ is selected from cycloalkyl, halo, aryl, andheteroaryl.
 21. The compound of claim 20, wherein R³ is selected frommethyl, chloro, and pyrazolo.
 22. The compound of claim 1, wherein B isaryl substituted with 0-3 occurrences of R².
 23. The compound of claim22, wherein B is phenyl substituted with 0-3 occurrences of R².
 24. Thecompound of claim 23, wherein B is unsubstituted phenyl.
 25. Thecompound of claim 23, wherein B is phenyl substituted with 1 occurrenceof R².
 26. The compound of claim 1, wherein R² is halo or alkyl.
 27. Thecompound of claim 1, wherein B is cycloalkyl.
 28. The compound of claim1, wherein B is heterocyclyl.
 29. The compound of claim 1, wherein Y isabsent, —O—, —N(R⁹)—, or —S(═O)₂—.
 30. The compound of claim 1, whereinX-Y is —CH₂—N(CH₃)—.
 31. The compound of claim 1, wherein X-Y is(S)—CH(CH₃)—NH—.
 32. The compound of claim 1, wherein X-Y is(R)—CH(CH₃)—NH—.
 33. The compound of claim 1, wherein X₁ is N.
 34. Thecompound of claim 1, wherein R¹⁰, R¹¹, R¹², R¹³ are independentlyselected from hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy,amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,and hydroxyl.
 35. The compound of claim 34, wherein R¹⁰, R¹¹, R¹², andR¹³ are independently selected from hydrogen, amino, and chloro.
 36. Thecompound of claim 35, wherein R¹⁰ is selected from amino and chloro. 37.The compound of claim
 1. wherein R⁸ is hydrogen.
 38. The compound ofclaim 1, wherein the compound is

or a pharmaceutically acceptable form thereof.
 39. The compound of claim1, wherein the compounds is

or a pharmaceutically acceptable form thereof.
 40. The compound of claim1, wherein the compounds is

or a pharmaceutically acceptable form thereof.
 41. The compound of claim1, wherein the compounds is

or a pharmaceutically acceptable form thereof.
 42. The compound of claim1, wherein the compounds is

or a pharmaceutically acceptable form thereof.
 43. The compound of claim1, wherein the compounds is

or a pharmaceutically acceptable form thereof.
 44. A compound selectedfrom

or a pharmaceutically acceptable form thereof.
 45. A compound selectedfrom

or a pharmaceutically acceptable form thereof.
 46. The compound of claim45, wherein the compound is

or a pharmaceutically acceptable form thereof.
 47. The compound of claim39, wherein the compound is

or a pharmaceutically acceptable form thereof.
 48. The compound of claim39, wherein the compound is

or a pharmaceutically acceptable form thereof.
 49. A pharmaceuticalcomposition comprising a compound according to claim 1 and one or morepharmaceutically acceptable excipients.
 50. A pharmaceutical compositioncomprising a compound according to claim 38 and one or morepharmaceutically acceptable excipients.
 51. A pharmaceutical compositioncomprising a compound according to claim 39 and one or morepharmaceutically acceptable excipients.
 52. A pharmaceutical compositioncomprising a compound according to claim 44 and one or morepharmaceutically acceptable excipients.
 53. A pharmaceutical compositioncomprising a compound according to claim 45 and one or morepharmaceutically acceptable excipients.
 54. A pharmaceutical compositioncomprising a compound according to claim 46 and one or morepharmaceutically acceptable excipients.
 55. A pharmaceutical compositioncomprising a compound according to claim 47 and one or morepharmaceutically acceptable excipients.
 56. A pharmaceutical compositioncomprising a compound according to claim 48 and one or morepharmaceutically acceptable excipients.